Siddhartha Jaiswal

All Publications

• Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes. Nature cardiovascular research Rauch, P. J., Gopakumar, J., Silver, A. J., Nachun, D., Ahmad, H., McConkey, M., Nakao, T., Bosse, M., Rentz, T., Vivanco Gonzalez, N., Greenwald, N. F., McCaffrey, E. F., Khair, Z., Gopakumar, M., Rodrigues, K. B., Lin, A. E., Sinha, E., Fefer, M., Cohen, D. N., Vromman, A., Shvartz, E., Sukhova, G., Bendall, S., Angelo, M., Libby, P., Ebert, B. L., Jaiswal, S. 2023; 2 (9): 805-818

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.

  View details for DOI 10.1038/s44161-023-00326-7

  View details for PubMedID 39196062

  View details for PubMedCentralID 8050831

• Clonal hematopoiesis is associated with protection from Alzheimer's disease. Nature medicine Bouzid, H., Belk, J. A., Jan, M., Qi, Y., Sarnowski, C., Wirth, S., Ma, L., Chrostek, M. R., Ahmad, H., Nachun, D., Yao, W., Beiser, A., Bick, A. G., Bis, J. C., Fornage, M., Longstreth, W. T., Lopez, O. L., Natarajan, P., Psaty, B. M., Satizabal, C. L., Weinstock, J., Larson, E. B., Crane, P. K., Keene, C. D., Seshadri, S., Satpathy, A. T., Montine, T. J., Jaiswal, S. 2023

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer's disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10-5), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.

  View details for DOI 10.1038/s41591-023-02397-2

  View details for PubMedID 37322115

  View details for PubMedCentralID 4306669

• Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. Nature Weinstock, J. S., Gopakumar, J., Burugula, B. B., Uddin, M. M., Jahn, N., Belk, J. A., Bouzid, H., Daniel, B., Miao, Z., Ly, N., Mack, T. M., Luna, S. E., Prothro, K. P., Mitchell, S. R., Laurie, C. A., Broome, J. G., Taylor, K. D., Guo, X., Sinner, M. F., von Falkenhausen, A. S., Kääb, S., Shuldiner, A. R., O'Connell, J. R., Lewis, J. P., Boerwinkle, E., Barnes, K. C., Chami, N., Kenny, E. E., Loos, R. J., Fornage, M., Hou, L., Lloyd-Jones, D. M., Redline, S., Cade, B. E., Psaty, B. M., Bis, J. C., Brody, J. A., Silverman, E. K., Yun, J. H., Qiao, D., Palmer, N. D., Freedman, B. I., Bowden, D. W., Cho, M. H., DeMeo, D. L., Vasan, R. S., Yanek, L. R., Becker, L. C., Kardia, S. L., Peyser, P. A., He, J., Rienstra, M., Van der Harst, P., Kaplan, R., Heckbert, S. R., Smith, N. L., Wiggins, K. L., Arnett, D. K., Irvin, M. R., Tiwari, H., Cutler, M. J., Knight, S., Muhlestein, J. B., Correa, A., Raffield, L. M., Gao, Y., de Andrade, M., Rotter, J. I., Rich, S. S., Tracy, R. P., Konkle, B. A., Johnsen, J. M., Wheeler, M. M., Smith, J. G., Melander, O., Nilsson, P. M., Custer, B. S., Duggirala, R., Curran, J. E., Blangero, J., McGarvey, S., Williams, L. K., Xiao, S., Yang, M., Gu, C. C., Chen, Y. I., Lee, W. J., Marcus, G. M., Kane, J. P., Pullinger, C. R., Shoemaker, M. B., Darbar, D., Roden, D. M., Albert, C., Kooperberg, C., Zhou, Y., Manson, J. E., Desai, P., Johnson, A. D., Mathias, R. A., Blackwell, T. W., Abecasis, G. R., Smith, A. V., Kang, H. M., Satpathy, A. T., Natarajan, P., Kitzman, J. O., Whitsel, E. A., Reiner, A. P., Bick, A. G., Jaiswal, S. 2023

  Abstract

  Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

  View details for DOI 10.1038/s41586-023-05806-1

  View details for PubMedID 37046083

  View details for PubMedCentralID 4624443

• Clonal hematopoiesis in human aging and disease SCIENCE Jaiswal, S., Ebert, B. L. 2019; 366 (6465): 586-+

  Abstract

  As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called "clonal hematopoiesis," is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

  View details for DOI 10.1126/science.aan4673

  View details for Web of Science ID 000494465700037

  View details for PubMedID 31672865

• PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells BLOOD Kahn, J. D., Miller, P. G., Silver, A. J., Sellar, R. S., Bhatt, S., Gibson, C., McConkey, M., Adams, D., Mar, B., Mertins, P., Fereshetian, S., Krug, K., Zhu, H., Letai, A., Carr, S. A., Doench, J., Jaiswal, S., Ebert, B. L. 2018; 132 (11): 1095–1105

  Abstract

  Truncating mutations in the terminal exon of protein phosphatase Mg2+/Mn2+ 1D (PPM1D) have been identified in clonal hematopoiesis and myeloid neoplasms, with a striking enrichment in patients previously exposed to chemotherapy. In this study, we demonstrate that truncating PPM1D mutations confer a chemoresistance phenotype, resulting in the selective expansion of PPM1D-mutant hematopoietic cells in the presence of chemotherapy in vitro and in vivo. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease mutational profiling of PPM1D in the presence of chemotherapy selected for the same exon 6 mutations identified in patient samples. These exon 6 mutations encode for a truncated protein that displays elevated expression and activity due to loss of a C-terminal degradation domain. Global phosphoproteomic profiling revealed altered phosphorylation of target proteins in the presence of the mutation, highlighting multiple pathways including the DNA damage response (DDR). In the presence of chemotherapy, PPM1D-mutant cells have an abrogated DDR resulting in altered cell cycle progression, decreased apoptosis, and reduced mitochondrial priming. We demonstrate that treatment with an allosteric, small molecule inhibitor of PPM1D reverts the phosphoproteomic, DDR, apoptotic, and mitochondrial priming changes observed in PPM1D-mutant cells. Finally, we show that the inhibitor preferentially kills PPM1D-mutant cells, sensitizes the cells to chemotherapy, and reverses the chemoresistance phenotype. These results provide an explanation for the enrichment of truncating PPM1D mutations in the blood of patients exposed to chemotherapy and in therapy-related myeloid neoplasms, and demonstrate that PPM1D can be a targeted in the prevention of clonal expansion of PPM1D-mutant cells and the treatment of PPM1D-mutant disease.

  View details for PubMedID 29954749

  View details for PubMedCentralID PMC6137556

• Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. The New England journal of medicine Jaiswal, S., Natarajan, P., Silver, A. J., Gibson, C. J., Bick, A. G., Shvartz, E., McConkey, M., Gupta, N., Gabriel, S., Ardissino, D., Baber, U., Mehran, R., Fuster, V., Danesh, J., Frossard, P., Saleheen, D., Melander, O., Sukhova, G. K., Neuberg, D., Libby, P., Kathiresan, S., Ebert, B. L. 2017; 377 (2): 111-121

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice.In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).

  View details for DOI 10.1056/NEJMoa1701719

  View details for PubMedID 28636844

• Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes BLOOD Steensma, D. P., Bejar, R., Jaiswal, S., Lindsley, R. C., Sekeres, M. A., Hasserjian, R. P., Ebert, B. L. 2015; 126 (1): 9-16

  Abstract

  Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies.

  View details for DOI 10.1182/blood-2015-03-631747

  View details for Web of Science ID 000357696200006

  View details for PubMedID 25931582

  View details for PubMedCentralID PMC4624443

• Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes NEW ENGLAND JOURNAL OF MEDICINE Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., Higgins, J. M., Moltchanov, V., Kuo, F. C., Kluk, M. J., Henderson, B., Kinnunen, L., Koistinen, H. A., Ladenvall, C., Getz, G., Correa, A., Banahan, B. F., Gabriel, S., Kathiresan, S., Stringham, H. M., McCarthy, M. I., Boehnke, M., Tuomilehto, J., Haiman, C., Groop, L., Atzmon, G., Wilson, J. G., Neuberg, D., Altshuler, D., Ebert, B. L. 2014; 371 (26): 2488-2498

  Abstract

  The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders.We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events.Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8).Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).

  View details for DOI 10.1056/NEJMoa1408617

  View details for Web of Science ID 000346920300008

  View details for PubMedID 25426837

  View details for PubMedCentralID PMC4306669

• CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis CELL Jaiswal, S., Jamieson, C. H., Pang, W. W., Park, C. Y., Chao, M. P., Majeti, R., Traver, D., van Rooijen, N., Weissman, I. L. 2009; 138 (2): 271-285

  Abstract

  Macrophages clear pathogens and damaged or aged cells from the blood stream via phagocytosis. Cell-surface CD47 interacts with its receptor on macrophages, SIRPalpha, to inhibit phagocytosis of normal, healthy cells. We find that mobilizing cytokines and inflammatory stimuli cause CD47 to be transiently upregulated on mouse hematopoietic stem cells (HSCs) and progenitors just prior to and during their migratory phase, and that the level of CD47 on these cells determines the probability that they are engulfed in vivo. CD47 is also constitutively upregulated on mouse and human myeloid leukemias, and overexpression of CD47 on a myeloid leukemia line increases its pathogenicity by allowing it to evade phagocytosis. We conclude that CD47 upregulation is an important mechanism that provides protection to normal HSCs during inflammation-mediated mobilization, and that leukemic progenitors co-opt this ability in order to evade macrophage killing.

  View details for DOI 10.1016/j.cell.2009.05.046

  View details for Web of Science ID 000268277000010

  View details for PubMedID 19632178

  View details for PubMedCentralID PMC2775564

• Clonal hematopoiesis of indeterminate potential and cardiovascular disease: Pathogenesis, clinical presentation, and future directions. Progress in cardiovascular diseases Gajagowni, S., Hopkins, S., Qadeer, Y., Virani, S. S., Verdonschot, J. A., Coombs, C. C., Amos, C. I., Nead, K. T., Jaiswal, S., Krittanawong, C. 2024

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is a well-studied phenomenon in hematologic malignancies. With advancements in gene sampling and analysis and the use of large cohort studies, CHIP has recently been linked to cardiovascular disease (CVD). The relationship between CHIP and CVD appears to be bidirectional, with traditional risk factors for cardiovascular disease increasing the mutation burden in CHIP, and CHIP itself effecting the incidence or prognosis of a variety of CVD. The purpose of this review is to understand the epidemiology, risk factors, and pathogenesis of CHIP in the context of various CVD conditions.

  View details for DOI 10.1016/j.pcad.2024.09.001

  View details for PubMedID 39278303

• Gene-Specific Machine Learning Models to Classify Driver Mutations in Clonal Hematopoiesis. Cancer discovery Arends, C. M., Jaiswal, S. 2024; 14 (9): 1581-1583

  Abstract

  There is no general consensus on the set of mutations capable of driving the age-related clonal expansions in hematopoietic stem cells known as clonal hematopoiesis, and current variant classifications typically rely on rules derived from expert knowledge. In this issue of Cancer Discovery, Damajo and colleagues trained and validated machine learning models without prior knowledge of clonal hematopoiesis driver mutations to classify somatic mutations in blood for 12 genes in a purely data-driven way. See related article by Demajo et al., p. 1717 (9).

  View details for DOI 10.1158/2159-8290.CD-24-0751

  View details for PubMedID 39228297

• The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations. medRxiv : the preprint server for health sciences Weinstock, J. S., Chaudhry, S. A., Ioannou, M., Viskadourou, M., Reventun, P., Jakubek, Y. A., Alexander Liggett, L., Laurie, C., Broome, J. G., Khan, A., Taylor, K. D., Guo, X., Peyser, P. A., Boerwinkle, E., Chami, N., Kenny, E. E., Loos, R. J., Psaty, B. M., Russell, T. P., Brody, J. A., Yun, J. H., Cho, M. H., Vasan, R. S., Kardia, S. L., Smith, J. A., Raffield, L. M., Bidulescu, A., O'Brien, E., de Andrade, M., Rotter, J. I., Rich, S. S., Tracy, R. P., Chen, Y. D., Gu, C. C., Hsiung, C. A., Kooperberg, C., Haring, B., Nassir, R., Mathias, R., Reiner, A., Sankaran, V., Lowenstein, C. J., Blackwell, T. W., Abecasis, G. R., Smith, A. V., Kang, H. M., Natarajan, P., Jaiswal, S., Bick, A., Post, W. S., Scheet, P., Auer, P., Karantanos, T., Battle, A., Arvanitis, M. 2024

  Abstract

  Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg ( TCL1A, TERT, SMC4, NRIP1, PRDM16 , MSRA , SCARB1 ), and one locus associated with a sex-associated mutation pathway ( SRGAP2C) . We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

  View details for DOI 10.1101/2024.08.22.24312319

  View details for PubMedID 39228737

• Dynamics of clonal hematopoiesis and risk of hematologic malignancy. International journal of hematology Arends, C. M., Jaiswal, S. 2024

  Abstract

  The age-related expansion of hematopoietic stem cell clones carrying somatic mutations is known as clonal hematopoiesis and is linked to hematologic malignancies, cardiovascular diseases, and increased mortality. As the risk for adverse outcomes increases substantially with clone size, a precise understanding of the mechanisms that promote clonal expansion is crucial to identify potential therapeutic targets. Clonal expansion and progression to myeloid malignancies are driven by a complex interplay of cell-intrinsic and extrinsic factors that remain incompletely understood. Here, we review how recently proposed methods to estimate clonal expansion rates have been implemented to study the natural history of clonal hematopoiesis and identify factors that promote clonal expansion. We discuss how these factors relate to progression to myeloid malignancies and recapitulate recent risk prediction models. While we are still in the early stages of understanding clonal expansion, analysis of large-scale biobank data in combination with experimental models will help to discover causal factors promoting or suppressing clone growth, define mechanisms, and identify potential targets for clinical intervention in the future.

  View details for DOI 10.1007/s12185-024-03829-6

  View details for PubMedID 39112743

• In Memoriam: Charles Chan. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Ambrosi, T. H., Jaiswal, S., Greenblatt, M. B. 2024

  View details for DOI 10.1093/jbmr/zjae095

  View details for PubMedID 39001686

• Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate. Nature aging Mack, T. M., Raddatz, M. A., Pershad, Y., Nachun, D. C., Taylor, K. D., Guo, X., Shuldiner, A. R., O'Connell, J. R., Kenny, E. E., Loos, R. J., Redline, S., Cade, B. E., Psaty, B. M., Bis, J. C., Brody, J. A., Silverman, E. K., Yun, J. H., Cho, M. H., DeMeo, D. L., Levy, D., Johnson, A. D., Mathias, R. A., Yanek, L. R., Heckbert, S. R., Smith, N. L., Wiggins, K. L., Raffield, L. M., Carson, A. P., Rotter, J. I., Rich, S. S., Manichaikul, A. W., Gu, C. C., Chen, Y. I., Lee, W. J., Shoemaker, M. B., Roden, D. M., Kooperberg, C., Auer, P. L., Desai, P., Blackwell, T. W., Smith, A. V., Reiner, A. P., Jaiswal, S., Weinstock, J. S., Bick, A. G. 2024

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

  View details for DOI 10.1038/s43587-024-00647-7

  View details for PubMedID 38834882

  View details for PubMedCentralID 4961884

• Determinants of mosaic chromosomal alteration fitness. Nature communications Pershad, Y., Mack, T., Poisner, H., Jakubek, Y. A., Stilp, A. M., Mitchell, B. D., Lewis, J. P., Boerwinkle, E., Loos, R. J., Chami, N., Wang, Z., Barnes, K., Pankratz, N., Fornage, M., Redline, S., Psaty, B. M., Bis, J. C., Shojaie, A., Silverman, E. K., Cho, M. H., Yun, J. H., DeMeo, D., Levy, D., Johnson, A. D., Mathias, R. A., Taub, M. A., Arnett, D., North, K. E., Raffield, L. M., Carson, A. P., Doyle, M. F., Rich, S. S., Rotter, J. I., Guo, X., Cox, N. J., Roden, D. M., Franceschini, N., Desai, P., Reiner, A. P., Auer, P. L., Scheet, P. A., Jaiswal, S., Weinstock, J. S., Bick, A. G. 2024; 15 (1): 3800

  Abstract

  Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

  View details for DOI 10.1038/s41467-024-48190-8

  View details for PubMedID 38714703

  View details for PubMedCentralID PMC11076528

• Radon Exposure, Clonal Hematopoiesis, and Stroke Susceptibility in the Women's Health Initiative. Neurology Anthony, K. M., Collins, J. M., Love, S. M., Stewart, J. D., Buchheit, S. F., Gondalia, R., Schwartz, G. G., Huang, D. Y., Meliker, J. R., Zhang, Z., Barac, A., Desai, P., Hayden, K. M., Honigberg, M. C., Jaiswal, S., Natarajan, P., Bick, A. G., Kooperberg, C., Manson, J. E., Reiner, A. P., Whitsel, E. A. 2024; 102 (2): e208055

  Abstract

  Studies suggest that clonal hematopoiesis of indeterminate potential (CHIP) may increase risk of hematologic malignancy and cardiovascular disease, including stroke. However, few studies have investigated plausible environmental risk factors for CHIP such as radon, despite the climate-related increases in and documented infrequency of testing for this common indoor air pollutant.The purpose of this study was to estimate the risk of CHIP related to radon, an established environmental mutagen.We linked geocoded addresses of 10,799 Women's Health Initiative Trans-Omics for Precision Medicine (WHI TOPMed) participants to US Environmental Protection Agency-predicted, county-level, indoor average screening radon concentrations, categorized as follows: Zone 1 (>4 pCi/L), Zone 2 (2-4 pCi/L), and Zone 3 (<2 pCi/L). We defined CHIP as the presence of one or more leukemogenic driver mutations with variant allele frequency >0.02. We identified prevalent and incident ischemic and hemorrhagic strokes; subtyped ischemic stroke using Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria; and then estimated radon-related risk of CHIP as an odds ratio (OR) and 95% CI using multivariable-adjusted, design-weighted logistic regression stratified by age, race/ethnicity, smoking status, and stroke type/subtype.The percentages of participants with CHIP in Zones 1, 2, and 3 were 9.0%, 8.4%, and 7.7%, respectively (ptrend = 0.06). Among participants with ischemic stroke, Zones 2 and 1 were associated with higher estimated risks of CHIP relative to Zone 3: 1.39 (1.15-1.68) and 1.46 (1.15-1.87), but not among participants with hemorrhagic stroke: 0.98 (0.68-1.40) and 1.03 (0.70-1.52), or without stroke: 1.04 (0.74-1.46) and 0.95 (0.63-1.42), respectively (pinteraction = 0.03). Corresponding estimates were particularly high among TOAST-subtyped cardioembolism: 1.78 (1.30-2.47) and 1.88 (1.31-2.72), or other ischemic etiologies: 1.37 (1.06-1.78) and 1.50 (1.11-2.04), but not small vessel occlusion: 1.05 (0.74-1.49) and 1.00 (0.68-1.47), respectively (pinteraction = 0.10). Observed patterns of association among strata were insensitive to attrition weighting, ancestry adjustment, prevalent stroke exclusion, separate analysis of DNMT3A driver mutations, and substitution with 3 alternative estimates of radon exposure.The robust elevation of radon-related risk of CHIP among postmenopausal women who develop incident cardioembolic stroke is consistent with a potential role of somatic genomic mutation in this societally burdensome form of cerebrovascular disease, although the mechanism has yet to be confirmed.

  View details for DOI 10.1212/WNL.0000000000208055

  View details for PubMedID 38170948

• Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study. European heart journal Ahn, H. J., An, H. Y., Ryu, G., Lim, J., Sun, C., Song, H., Choi, S. Y., Lee, H., Maurer, T., Nachun, D., Kwon, S., Lee, S. R., Lip, G. Y., Oh, S., Jaiswal, S., Koh, Y., Choi, E. K. 2024

  Abstract

  Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF.Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes-the composite of heart failure, ischaemic stroke, or death-according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort.The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10-1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14-1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05-2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E', and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death).CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.

  View details for DOI 10.1093/eurheartj/ehad869

  View details for PubMedID 38231881

• Individual and Neighborhood-level Socioeconomic Status and Somatic Mutations Associated With Increased Risk of Cardiovascular Disease and Mortality: A Cross-Sectional Analysis in the Women's Health Initiative. Women's health issues : official publication of the Jacobs Institute of Women's Health Love, S. M., Collins, J. M., Anthony, K. M., Buchheit, S. F., Butler, E. N., Bey, G. S., Gondalia, R., Hayden, K. M., Zannas, A. S., Bick, A. G., Manson, J. E., Desai, P. M., Natarajan, P., Bhattacharya, R., Jaiswal, S., Barac, A., Reiner, A., Kooperberg, C., Stewart, J. D., Whitsel, E. A. 2023

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of leukemogenic mutations in white blood cells, has been associated with increased risk of atherosclerotic cardiovascular diseases, cancer, and mortality.We examined the relationship between individual- and neighborhood-level socioeconomic status (SES) and CHIP and evaluated effect modification by interpersonal and intrapersonal resources.The study population included 10,799 postmenopausal women from the Women's Health Initiative without hematologic malignancy or antineoplastic medication use. Individual- and neighborhood (Census tract)-level SES were assessed across several domains including education, income, and occupation, and a neighborhood-level SES summary z-score, which captures multiple dimensions of SES, was generated. Interpersonal and intrapersonal resources were self-reports. CHIP was ascertained based on a prespecified list of leukemogenic driver mutations. Weighted logistic regression models adjusted for covariates were used to estimate risk of CHIP as an odds ratio (OR) and 95% confidence interval (95% CI).The interval-scale neighborhood-level SES summary z-score was associated with a 3% increased risk of CHIP: OR (95% CI) = 1.03 (1.00-1.05), p = .038. Optimism significantly modified that estimate, such that among women with low/medium and high levels of optimism, the corresponding ORs (95% CIs) were 1.03 (1.02-1.04) and 0.95 (0.94-0.96), pInteraction < .001.Our findings suggest that reduced risk of somatic mutation may represent a biological pathway by which optimism protects contextually advantaged but at-risk women against age-related chronic disease and highlight potential benefits of long-term, positive psychological interventions.

  View details for DOI 10.1016/j.whi.2023.10.005

  View details for PubMedID 38061917

• Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias. European heart journal Schuermans, A., Vlasschaert, C., Nauffal, V., Cho, S. M., Uddin, M. M., Nakao, T., Niroula, A., Klarqvist, M. D., Weeks, L. D., Lin, A. E., Saadatagah, S., Lannery, K., Wong, M., Hornsby, W., Lubitz, S. A., Ballantyne, C., Jaiswal, S., Libby, P., Ebert, B. L., Bick, A. G., Ellinor, P. T., Natarajan, P., Honigberg, M. C. 2023

  Abstract

  Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias.UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested.This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR.CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.

  View details for DOI 10.1093/eurheartj/ehad670

  View details for PubMedID 37952204

• Genetic modification of inflammation and clonal hematopoiesis-associated cardiovascular risk. The Journal of clinical investigation Yu, Z., Filder, T. P., Ruan, Y., Vlasschaert, C., Nakao, T., Uddin, M. M., Mack, T., Niroula, A., Heimlich, J. B., Zekavat, S. M., Gibson, C. J., Griffin, G. K., Wang, Y., Peloso, G. M., Heard-Costa, N., Levy, D., Vasan, R. S., Aguet, F., Ardlie, K. G., Taylor, K. D., Rich, S. S., Rotter, J. I., Libby, P., Jaiswal, S., Ebert, B. L., Bick, A. G., Tall, A. R., Natarajan, P. 2023

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVD), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. CHIP was identified using whole exome sequencing data of blood DNA and modeled both as a composite and for common drivers (DNMT3A, TET2, ASXL1, and JAK2) separately. We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identify IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risks. We show that CRISPR-induced Asxl1 mutated murine macrophages have a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVD protective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides new evidence to support gene-specific strategies to address CHIP-associated CVD risk.

  View details for DOI 10.1172/JCI168597

  View details for PubMedID 37498674

• Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Gumuser, E. D., Schuermans, A., Cho, S., Sporn, Z. A., Uddin, M., Paruchuri, K., Nakao, T., Yu, Z., Haidermota, S., Hornsby, W., Weeks, L. D., Niroula, A., Jaiswal, S., Libby, P., Ebert, B. L., Bick, A. G., Natarajan, P., Honigberg, M. C. 2023; 81 (20): 1996-2009

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP)-the age-related clonal expansion of blood stem cells with leukemia-associated mutations-is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear.This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD.Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression.Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001).CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

  View details for DOI 10.1016/j.jacc.2023.03.401

  View details for Web of Science ID 001002154400001

  View details for PubMedID 37197843

  View details for PubMedCentralID PMC10249057

• Clonal haematopoiesis and atherosclerotic cardiovascular disease NATURE REVIEWS CARDIOLOGY Ahmad, H., Jaiswal, S. 2023; 20 (7): 437-438

  View details for DOI 10.1038/s41569-023-00882-2

  View details for Web of Science ID 000986067400002

  View details for PubMedID 37169832

  View details for PubMedCentralID 4306669

• Prediction of risk for myeloid malignancy in clonal hematopoiesis. NEJM evidence Weeks, L. D., Niroula, A., Neuberg, D., Wong, W., Lindsley, R. C., Luskin, M., Berliner, N., Stone, R. M., DeAngelo, D. J., Soiffer, R., Uddin, M. M., Griffin, G., Vlasschaert, C., Gibson, C. J., Jaiswal, S., Bick, A. G., Malcovati, L., Natarajan, P., Ebert, B. L. 2023; 2 (5)

  Abstract

  Background: Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) ≥ 0.02, in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults and defining predictors of MN risk would aid clinical management and research.Methods: We analyzed sequenced exomes of healthy UK Biobank (UKB) participants (n = 438,890) in separate derivation and validation cohorts. Genetic mutations, laboratory values, and MN outcomes were used in conditional probability-based recursive partitioning and Cox regression to determine predictors of incident MN. Combined statistical weights defined a clonal hematopoiesis risk score (CHRS). Independent CHIP/CCUS patient cohorts were used to test prognostic capability of the CHRS in the clinical setting.Results: Recursive partitioning distinguished CHIP/CCUS cases with 10-year probabilities of MN ranging from 0.0078 - 0.85. Multivariable analysis validated partitioning variables as predictors of MN. Key features, including single DNMT3A mutations, high risk mutations, ≥ 2 mutations, VAF ≥ 0.2, age ≥ 65 years, CCUS vs CHIP and red blood cell indices, influenced MN risk in variable direction. The CHRS defined low risk (n = 10018, 88.4%), intermediate risk (n = 1196, 10.5%), and high risk (n = 123, 1.1%) groups. In clinical cohorts, most MN events occurred in high risk CHIP/CCUS patients.Conclusions: The CHRS provides simple prognostic framework for CHIP/CCUS, distinguishing a high risk minority from the majority of CHIP/CCUS which has minimal risk for progression to MN.

  View details for DOI 10.1056/evidoa2200310

  View details for PubMedID 37483562

• The genetic determinants of recurrent somatic mutations in 43,693 blood genomes. Science advances Weinstock, J. S., Laurie, C. A., Broome, J. G., Taylor, K. D., Guo, X., Shuldiner, A. R., O'Connell, J. R., Lewis, J. P., Boerwinkle, E., Barnes, K. C., Chami, N., Kenny, E. E., Loos, R. J., Fornage, M., Redline, S., Cade, B. E., Gilliland, F. D., Chen, Z., Gauderman, W. J., Kumar, R., Grammer, L., Schleimer, R. P., Psaty, B. M., Bis, J. C., Brody, J. A., Silverman, E. K., Yun, J. H., Qiao, D., Weiss, S. T., Lasky-Su, J., DeMeo, D. L., Palmer, N. D., Freedman, B. I., Bowden, D. W., Cho, M. H., Vasan, R. S., Johnson, A. D., Yanek, L. R., Becker, L. C., Kardia, S., He, J., Kaplan, R., Heckbert, S. R., Smith, N. L., Wiggins, K. L., Arnett, D. K., Irvin, M. R., Tiwari, H., Correa, A., Raffield, L. M., Gao, Y., de Andrade, M., Rotter, J. I., Rich, S. S., Manichaikul, A. W., Konkle, B. A., Johnsen, J. M., Wheeler, M. M., Custer, B. S., Duggirala, R., Curran, J. E., Blangero, J., Gui, H., Xiao, S., Williams, L. K., Meyers, D. A., Li, X., Ortega, V., McGarvey, S., Gu, C. C., Chen, Y. I., Lee, W. J., Shoemaker, M. B., Darbar, D., Roden, D., Albert, C., Kooperberg, C., Desai, P., Blackwell, T. W., Abecasis, G. R., Smith, A. V., Kang, H. M., Mathias, R., Natarajan, P., Jaiswal, S., Reiner, A. P., Bick, A. G. 2023; 9 (17): eabm4945

  Abstract

  Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

  View details for DOI 10.1126/sciadv.abm4945

  View details for PubMedID 37126548

• Clonal haematopoiesis and risk of chronic liver disease. Nature Wong, W. J., Emdin, C., Bick, A. G., Zekavat, S. M., Niroula, A., Pirruccello, J. P., Dichtel, L., Griffin, G., Uddin, M. M., Gibson, C. J., Kovalcik, V., Lin, A. E., McConkey, M. E., Vromman, A., Sellar, R. S., Kim, P. G., Agrawal, M., Weinstock, J., Long, M. T., Yu, B., Banerjee, R., Nicholls, R. C., Dennis, A., Kelly, M., Loh, P. R., McCarroll, S., Boerwinkle, E., Vasan, R. S., Jaiswal, S., Johnson, A. D., Chung, R. T., Corey, K., Levy, D., Ballantyne, C., Ebert, B. L., Natarajan, P. 2023

  Abstract

  Chronic liver disease is a major public health burden worldwide1. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis2. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response.

  View details for DOI 10.1038/s41586-023-05857-4

  View details for PubMedID 37046084

  View details for PubMedCentralID 4624443

• A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic datasets. Blood Vlasschaert, C., Mack, T., Heimlich, J. B., Niroula, A., Uddin, M. M., Weinstock, J. S., Sharber, B., Silver, A. J., Xu, Y., Savona, M. R., Gibson, C. J., Lanktree, M. B., Rauh, M. J., Ebert, B. L., Natarajan, P., Jaiswal, S., Bick, A. G. 2023

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples sequenced using approaches that cover the whole genome, whole exome or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germline variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and population-based associations to increase the accuracy of CHIP calls. We apply this approach to ascertain CHIP in ~550,000 individuals in the UK Biobank complete whole exome cohort and the All of Us Research Program initial whole genome release cohort. CHIP ascertainment on this scale unmasks recurrent artifactual variants and highlights the importance of specialized filtering approaches for several genes including TET2 and ASXL1. We show how small changes in filtering parameters can considerably increase CHIP misclassification and reduce the effect size of epidemiological associations. Our high-fidelity call set refines prior population-based associations of CHIP with incident outcomes. For example, the annualized incidence of myeloid malignancy in individuals with small CHIP clones is 0.03%/year, which increases to 0.5%/year amongst individuals with very large CHIP clones. We also find a significantly lower prevalence of CHIP in individuals of self-reported Latino or Hispanic ethnicity in All of Us, highlighting the importance of including diverse populations. The standardization of CHIP calling will increase the fidelity of CHIP epidemiological work and is required for clinical CHIP diagnostic assays.

  View details for DOI 10.1182/blood.2022018825

  View details for PubMedID 36652671

• Birth Weight Is Associated With Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Outcomes in Adulthood. Journal of the American Heart Association Schuermans, A., Nakao, T., Ruan, Y., Koyama, S., Yu, Z., Uddin, M. M., Haidermota, S., Hornsby, W., Lewandowski, A. J., Bick, A. G., Niroula, A., Jaiswal, S., Ebert, B. L., Natarajan, P., Honigberg, M. C. 2023; 12 (13): e030220

  Abstract

  Background High and low birth weight are independently associated with increased cardiovascular disease risk in adulthood. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with preleukemic somatic mutations, predicts incident cardiovascular disease independent of traditional cardiovascular risk factors. Whether birth weight predicts development of CHIP later in life is unknown. Methods and Results A total of 221047 adults enrolled in the UK Biobank with whole exome sequences and self-reported birth weight were analyzed. Of those, 22030 (11.5%) had low (<2.5kg) and 29292 (14.7%) high birth weight (>4.0kg). CHIP prevalence was higher among participants with low (6.0%, P=0.049) and high (6.3%, P<0.001) versus normal birth weight (5.7%, ref.). Multivariable-adjusted logistic regression analyses demonstrated that each 1-kg increase in birth weight was associated with a 3% increased risk of CHIP (odds ratio, 1.03 [95% CI, 1.00-1.06]; P=0.04), driven by a stronger association observed between birth weight and DNMT3A CHIP (odds ratio, 1.04 per 1-kg increase [95% CI, 1.01-1.08]; P=0.02). Mendelian randomization analyses supported a causal relationship of longer gestational age at delivery with DNMT3A CHIP. Multivariable Cox regression demonstrated that CHIP was independently and additively associated with incident cardiovascular disease or death across birth weight groups, with highest absolute risks in those with CHIP plus high or low birth weight. Conclusions Higher birth weight is associated with increased risk of developing CHIP in midlife, especially DNMT3A CHIP. These findings identify a novel risk factor for CHIP and provide insights into the relationships among early-life environment, CHIP, cancer, and cardiovascular disease.

  View details for DOI 10.1161/JAHA.123.030220

  View details for PubMedID 37345823

• Clonal Hematopoiesis and Its Impact on Human Health. Annual review of medicine Ahmad, H., Jahn, N., Jaiswal, S. 2022

  Abstract

  Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-med-042921-112347

  View details for PubMedID 36450282

• Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis Weeks, L. D., Niroula, A., Neuberg, D. S., Wong, W. J., Lindsley, R., Luskin, M. R., Berliner, N., Stone, R. M., DeAngelo, D. J., Soiffer, R. J., Uddin, M., Gibson, C. J., Bick, A. G., Griffin, G. K., Jaiswal, S., Malcovati, L., Natarajan, P., Ebert, B. L. AMER SOC HEMATOLOGY. 2022: 2229-2231

  View details for DOI 10.1182/blood-2022-158960

  View details for Web of Science ID 000893223202101

• Genomic Profiling for Clinical Decision Making in Myeloid Neoplasms and Acute Leukemia. Blood Duncavage, E. J., Bagg, A., Hasserjian, R. P., DiNardo, C. D., Godley, L. A., Iacobucci, I., Jaiswal, S., Malcovati, L., Vannucchi, A. M., Patel, K. P., Arber, D. A., Arcila, M. E., Bejar, R., Berliner, N., Borowitz, M. J., Branford, S., Brown, A. L., Cargo, C. A., Dohner, H., Falini, B., Garcia-Manero, G., Haferlach, T., Hellstrom-Lindberg, E., Kim, A. S., Klco, J. M., Komrokji, R. S., Loh, M. L., Loghavi, S., Mullighan, C. G., Ogawa, S., Tefferi, A., Papaemmanuil, E., Reiter, A., Ross, D. M., Savona, M. R., Shimamura, A., Skoda, R. C., Sole, F., Stone, R. M., Orazi, A., Walter, M. J., Wu, D., Ebert, B. L., Cazzola, M. 2022

  Abstract

  Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. While assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the last several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole exome sequencing (WES), whole genome sequencing (WGS), and whole transcriptome sequencing (WTS) or RNAseq. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are employed not only for detecting somatically acquired gene mutations, but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias makes extensive use of genomic data. This report aims to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with these hematologic neoplasms.

  View details for DOI 10.1182/blood.2022015853

  View details for PubMedID 36130297

• Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease. Nature communications Uddin, M. D., Nguyen, N. Q., Yu, B., Brody, J. A., Pampana, A., Nakao, T., Fornage, M., Bressler, J., Sotoodehnia, N., Weinstock, J. S., Honigberg, M. C., Nachun, D., Bhattacharya, R., Griffin, G. K., Chander, V., Gibbs, R. A., Rotter, J. I., Liu, C., Baccarelli, A. A., Chasman, D. I., Whitsel, E. A., Kiel, D. P., Murabito, J. M., Boerwinkle, E., Ebert, B. L., Jaiswal, S., Floyd, J. S., Bick, A. G., Ballantyne, C. M., Psaty, B. M., Natarajan, P., Conneely, K. N. 2022; 13 (1): 5350

  Abstract

  Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

  View details for DOI 10.1038/s41467-022-33093-3

  View details for PubMedID 36097025

• TET2-mutant clonal hematopoiesis and risk of gout. Blood Agrawal, M., Niroula, A., Cunin, P., McConkey, M., Kovalcik, V., Kim, P. G., Wong, W. J., Weeks, L. D., Lin, A. E., Miller, P. G., Gibson, C. J., Sekar, A., Schaefer, I., Neuberg, D., Stone, R. M., Bick, A. G., Uddin, M. M., Griffin, G. K., Jaiswal, S., Natarajan, P., Nigrovic, P. A., Rao, D. A., Ebert, B. L. 2022

  Abstract

  Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of pro-inflammatory cytokines, including interleukin-1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1B, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177,824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: OR, 1.69; 95% CI, 1.09-2.61; P=0.0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P=0.0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: HR, 1.28; 95% CI, 1.06-1.55; P=0.0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1B secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1B in response to MSU crystals in vitro, and this was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1B levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in gout patients.

  View details for DOI 10.1182/blood.2022015384

  View details for PubMedID 35714308

• Modeling the temporal dynamics of clonal hematopoiesis. Nature cardiovascular research Jaiswal, S., Bick, A. G. 2022; 1 (6): 537-538

  View details for DOI 10.1038/s44161-022-00086-w

  View details for PubMedID 39195865

  View details for PubMedCentralID 9177423

• Modeling the temporal dynamics of clonal hematopoiesis NATURE CARDIOVASCULAR RESEARCH Jaiswal, S., Bick, A. G. 2022; 1 (6): 537-538

  View details for DOI 10.1038/s44161-022-00086-w

  View details for Web of Science ID 001124964000009

• Longitudinal profiling of clonal hematopoiesis provides insight into clonal dynamics IMMUNITY & AGEING Uddin, M., Zhou, Y., Bick, A. G., Burugula, B., Jaiswal, S., Desai, P., Honigberg, M. C., Love, S., Barac, A., Hayden, K. M., Manson, J. E., Whitsel, E. A., Kooperberg, C., Natarajan, P., Reiner, A. P., Kitzman, J. O. 2022; 19 (1): 23

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to those assays' high cost, most population studies have been cross-sectional, sequencing only a single timepoint per individual.We developed and validated a cost-effective single molecule molecular inversion probe sequencing (smMIPS) assay for detecting CHIP, targeting the 11 most frequently mutated genes in CHIP along with 4 recurrent mutational hotspots. We sequenced 548 multi-timepoint samples collected from 182 participants in the Women's Health Initiative cohort, across a median span of 16 years. We detected 178 driver mutations reaching variant allele frequency ≥ 2% in at least one timepoint, many of which were detectable well below this threshold at earlier timepoints. The majority of clonal mutations (52.1%) expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy.Targeted smMIPS sequencing can sensitively measure clonal dynamics in CHIP. Mutations that reached the conventional threshold for CHIP (2% frequency) tended to continue growing, indicating that after CHIP is acquired, it is generally not lost. The ability to cost-effectively profile CHIP longitudinally will enable future studies to investigate why some CHIP clones expand, and how their dynamics relate to health outcomes at a biobank scale.

  View details for DOI 10.1186/s12979-022-00278-9

  View details for Web of Science ID 000801152700001

  View details for PubMedID 35610705

• Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self. Circulation research Roy Chowdhury, R., D'Addabbo, J., Huang, X., Veizades, S., Sasagawa, K., Louis, D. M., Cheng, P., Sokol, J., Jensen, A., Tso, A., Shankar, V., Wendel, B. S., Bakerman, I., Liang, G., Koyano, T., Fong, R., Nau, A., Ahmad, H., Gopakumar, J. K., Wirka, R., Lee, A., Boyd, J., Woo, Y. J., Quertermous, T., Gulati, G., Jaiswal, S., Chien, Y. H., Chan, C., Davis, M. M., Nguyen, P. K. 2022: 101161CIRCRESAHA121320090

  Abstract

  Once considered primarily a disorder of lipid deposition, coronary artery disease is an incurable, life-threatening disease that is now also characterized by chronic inflammation notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies.We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression of CCR7 and L-selectin, indicating that they are primarily antigen-experienced, memory cells. Notably, nearly one-third of these cells express the HLA-DRA surface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4

  View details for DOI 10.1161/CIRCRESAHA.121.320090

  View details for PubMedID 35430876

• Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential. Science advances Nakao, T., Bick, A. G., Taub, M. A., Zekavat, S. M., Uddin, M. M., Niroula, A., Carty, C. L., Lane, J., Honigberg, M. C., Weinstock, J. S., Pampana, A., Gibson, C. J., Griffin, G. K., Clarke, S. L., Bhattacharya, R., Assimes, T. L., Emery, L. S., Stilp, A. M., Wong, Q., Broome, J., Laurie, C. A., Khan, A. T., Smith, A. V., Blackwell, T. W., Codd, V., Nelson, C. P., Yoneda, Z. T., Peralta, J. M., Bowden, D. W., Irvin, M. R., Boorgula, M., Zhao, W., Yanek, L. R., Wiggins, K. L., Hixson, J. E., Gu, C. C., Peloso, G. M., Roden, D. M., Reupena, M. S., Hwu, C., DeMeo, D. L., North, K. E., Kelly, S., Musani, S. K., Bis, J. C., Lloyd-Jones, D. M., Johnsen, J. M., Preuss, M., Tracy, R. P., Peyser, P. A., Qiao, D., Desai, P., Curran, J. E., Freedman, B. I., Tiwari, H. K., Chavan, S., Smith, J. A., Smith, N. L., Kelly, T. N., Hidalgo, B., Cupples, L. A., Weeks, D. E., Hawley, N. L., Minster, R. L., Samoan Obesity, L. a., Deka, R., Naseri, T. T., de Las Fuentes, L., Raffield, L. M., Morrison, A. C., Vries, P. S., Ballantyne, C. M., Kenny, E. E., Rich, S. S., Whitsel, E. A., Cho, M. H., Shoemaker, M. B., Pace, B. S., Blangero, J., Palmer, N. D., Mitchell, B. D., Shuldiner, A. R., Barnes, K. C., Redline, S., Kardia, S. L., Abecasis, G. R., Becker, L. C., Heckbert, S. R., He, J., Post, W., Arnett, D. K., Vasan, R. S., Darbar, D., Weiss, S. T., McGarvey, S. T., de Andrade, M., Chen, Y. I., Kaplan, R. C., Meyers, D. A., Custer, B. S., Correa, A., Psaty, B. M., Fornage, M., Manson, J. E., Boerwinkle, E., Konkle, B. A., Loos, R. J., Rotter, J. I., Silverman, E. K., Kooperberg, C., Danesh, J., Samani, N. J., Jaiswal, S., Libby, P., Ellinor, P. T., Pankratz, N., Ebert, B. L., Reiner, A. P., Mathias, R. A., Do, R., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Natarajan, P. 2022; 8 (14): eabl6579

  Abstract

  Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.

  View details for DOI 10.1126/sciadv.abl6579

  View details for PubMedID 35385311

• Clonal Hematopoiesis Analyses in Clinical, Epidemiologic, and Genetic Aging Studies to Unravel Underlying Mechanisms of Age-Related Dysfunction in Humans. Frontiers in aging Walsh, K., Raghavachari, N., Kerr, C., Bick, A. G., Cummings, S. R., Druley, T., Dunbar, C. E., Genovese, G., Goodell, M. A., Jaiswal, S., Maciejewski, J., Natarajan, P., Shindyapina, A. V., Shuldiner, A. R., Van Den Akker, E. B., Vijg, J. 2022; 3: 841796

  Abstract

  Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that expand with age in otherwise normal tissues. In the hematopoietic system, this phenomenon has generally been referred to as "clonal hematopoiesis of indeterminate potential" (CHIP) when it applies to a subset of clones in which mutations in driver genes of hematologic malignancies are found. Other mechanisms of clonal hematopoiesis, including large chromosomal alterations, can also give rise to clonal expansion in the absence of conventional CHIP driver gene mutations. Both types of clonal hematopoiesis (CH) have been observed in studies of animal models and humans in association with altered immune responses, increased mortality, and disease risk. Studies in murine models have found that some of these clonal events are involved in abnormal inflammatory and metabolic changes, altered DNA damage repair and epigenetic changes. Studies in long-lived individuals also show the accumulation of somatic mutations, yet at this advanced age, carriership of somatic mutations is no longer associated with an increased risk of mortality. While it remains to be elucidated what factors modify this genotype-phenotype association, i.e., compensatory germline genetics, cellular context of the mutations, protective effects to diseases at exceptional age, it points out that the exceptionally long-lived are key to understand the phenotypic consequences of CHIP mutations. Assessment of the clinical significance of somatic mutations occurring in blood cell types for age-related outcomes in human populations of varied life and health span, environmental exposures, and germline genetic risk factors will be valuable in the development of personalized strategies tailored to specific somatic mutations for healthy aging.

  View details for DOI 10.3389/fragi.2022.841796

  View details for PubMedID 35821803

  View details for PubMedCentralID PMC9261374

• Clonal Hematopoiesis: Confluence of Malignant and Nonmalignant Diseases ANNUAL REVIEW OF CANCER BIOLOGY Lin, A. E., Rauch, P. J., Jaiswal, S., Ebert, B. L. 2022; 6: 187-200

  View details for DOI 10.1146/annurev-cancerbio-060121-120026

  View details for Web of Science ID 000789891800011

• Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis. The Journal of experimental medicine Kim, P. G., Niroula, A., Shkolnik, V., McConkey, M., Lin, A. E., Slabicki, M., Kemp, J. P., Bick, A., Gibson, C. J., Griffin, G., Sekar, A., Brooks, D. J., Wong, W. J., Cohen, D. N., Uddin, M. M., Shin, W. J., Pirruccello, J., Tsai, J. M., Agrawal, M., Kiel, D. P., Bouxsein, M. L., Richards, J. B., Evans, D. M., Wein, M. N., Charles, J. F., Jaiswal, S., Natarajan, P., Ebert, B. L. 2021; 218 (12)

  Abstract

  Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a-/- demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-kappaB-mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation.

  View details for DOI 10.1084/jem.20211872

  View details for PubMedID 34698806

• Clonal Hematopoiesis is Associated with Reduced Risk of Alzheimer's Disease Bouzid, H., Belk, J., Jan, M., Qi, Y., Sarnowski, C., Wirth, S., Ma, L., Chrostek, M., Ahmad, H., Nachun, D., Yao, W., Beiser, A., Bick, A. G., Bis, J., Fornage, M., Longstreth, W. T., Lopez, O., Nataranjan, P., Psaty, B., Satizabal, C., Weinstock, J., Larson, E., Crane, P., Keene, C., Seshadri, S., Satpathy, A. T., Montine, T., Jaiswal, S. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-151064

  View details for Web of Science ID 000736398800006

• Clonal Hematopoiesis Is Driven By Aberrant Activation of TCL1A Gopakumar, J. K., Weinstock, J., Burugula, B. B., Jahn, N., Kooperberg, C., Desai, P., Natarajan, P., Kitzman, J. O., Reiner, A., Bick, A. G., Jaiswal, S. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-153242

  View details for Web of Science ID 000736398802138

• ZBTB33 is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing. Blood cancer discovery Beauchamp, E. M., Leventhal, M., Bernard, E., Hoppe, E. R., Todisco, G., Creignou, M., Gallì, A., Castellano, C. A., McConkey, M., Tarun, A., Wong, W., Schenone, M., Stanclift, C., Tanenbaum, B., Malolepsza, E., Nilsson, B., Bick, A. G., Weinstock, J. S., Miller, M., Niroula, A., Dunford, A., Taylor-Weiner, A., Wood, T., Barbera, A., Anand, S., Psaty, B. M., Desai, P., Cho, M. H., Johnson, A. D., Loos, R., MacArthur, D. G., Lek, M., Neuberg, D. S., Lage, K., Carr, S. A., Hellstrom-Lindberg, E., Malcovati, L., Papaemmanuil, E., Stewart, C., Getz, G., Bradley, R. K., Jaiswal, S., Ebert, B. L. 2021; 2 (5): 500-517

  Abstract

  Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.

  View details for DOI 10.1158/2643-3230.BCD-20-0224

  View details for PubMedID 34568833

  View details for PubMedCentralID PMC8462124

• Infection makes micro-CHIPs into macro-CHIPs. Cell stem cell Gopakumar, J., Jaiswal, S. 2021; 28 (8): 1335-1336

  Abstract

  In this issue of Cell Stem Cell, Hormaechea-Agulla etal. (2021) demonstrate that IFNgamma signaling following an infection in mice provides a selective pressure that drives growth of Dnmt3a-/- hematopoietic stem cells. This clonal expansion is mediated by global methylation changes that lead to an increased self-renewing capacity.

  View details for DOI 10.1016/j.stem.2021.07.006

  View details for PubMedID 34358435

• Clonal hematopoiesis associated with epigenetic aging and clinical outcomes. Aging cell Nachun, D., Lu, A. T., Bick, A. G., Natarajan, P., Weinstock, J., Szeto, M. D., Kathiresan, S., Abecasis, G., Taylor, K. D., Guo, X., Tracy, R., Durda, P., Liu, Y., Johnson, C., Rich, S. S., Van Den Berg, D., Laurie, C., Blackwell, T., Papanicolaou, G. J., Correa, A., Raffield, L. M., Johnson, A. D., Murabito, J., Manson, J. E., Desai, P., Kooperberg, C., Assimes, T. L., Levy, D., Rotter, J. I., Reiner, A. P., Whitsel, E. A., Wilson, J. G., Horvath, S., Jaiswal, S., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium 2021: e13366

  Abstract

  Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31years (GrimAge, p<8.6*10-7 ) to 3.08years (EEAA, p<3.7*10-18 ). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p<4.1*10-8 ) and coronary heart disease (CHD) (hazard ratio 3.24, p<9.3*10-6 ) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG- were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.

  View details for DOI 10.1111/acel.13366

  View details for PubMedID 34050697

• Inherited causes of clonal haematopoiesis in 97,691 whole genomes (vol 586 , pg 763, 2020) NATURE Bick, A. G., Weinstock, J. S., Nandakumar, S. K., Fulco, C. P., Bao, E. L., Zekavat, S. M., Szeto, M. D., Liao, X., Leventhal, M. J., Nasser, J., Chang, K., Laurie, C., Burugula, B., Gibson, C. J., Niroula, A., Lin, A. E., Taub, M. A., Aguet, F., Ardlie, K., Mitchell, B. D., Barnes, K. C., Moscati, A., Fornage, M., Redline, S., Psaty, B. M., Silverman, E. K., Weiss, S. T., Palmer, N. D., Vasan, R. S., Burchard, E. G., Kardia, S. R., He, J., Kaplan, R. C., Smith, N. L., Arnett, D. K., Schwartz, D. A., Correa, A., de Andrade, M., Guo, X., Konkle, B. A., Custer, B., Peralta, J. M., Gui, H., Meyers, D. A., McGarvey, S. T., Chen, I., Shoemaker, M., Peyser, P. A., Broome, J. G., Gogarten, S. M., Wang, F., Wong, Q., Montasser, M. E., Daya, M., Kenny, E. E., North, K. E., Launer, L. J., Cade, B. E., Bis, J. C., Cho, M. H., Lasky-Su, J., Bowden, D. W., Cupples, L., Mak, A. Y., Becker, L. C., Smith, J. A., Kelly, T. N., Aslibekyan, S., Heckbert, S. R., Tiwari, H. K., Yang, I. V., Heit, J. A., Lubitz, S. A., Johnsen, J. M., Curran, J. E., Wenzel, S. E., Weeks, D. E., Rao, D. C., Darbar, D., Moon, J., Tracy, R. P., Buth, E. J., Rafaels, N., Loos, R. F., Durda, P., Liu, Y., Hou, L., Lee, J., Kachroo, P., Freedman, B. I., Levy, D., Bielak, L. F., Hixson, J. E., Floyd, J. S., Whitsel, E. A., Ellinor, P. T., Irvin, M. R., Fingerlin, T. E., Raffield, L. M., Armasu, S. M., Wheeler, M. M., Sabino, E. C., Blangero, J., Williams, L., Levy, B. D., Sheu, W., Roden, D. M., Boerwinkle, E., Manson, J. E., Mathias, R. A., Desai, P., Taylor, K. D., Johnson, A. D., Auer, P. L., Kooperberg, C., Laurie, C. C., Blackwell, T. W., Smith, A. V., Zhao, H., Lange, E., Lange, L., Rich, S. S., Rotter, J. I., Wilson, J. G., Scheet, P., Kitzman, J. O., Lander, E. S., Engreitz, J. M., Ebert, B. L., Reiner, A. P., Jaiswal, S., Abecasis, G., Sankaran, V. G., Kathiresan, S., Natarajan, P., NHLBI Trans Omi 2021; 591 (7851): E27

  View details for DOI 10.1038/s41586-021-03280

  View details for Web of Science ID 000632177100002

• Insights into clonal hematopoiesis and its relation to cancer risk. Current opinion in genetics & development Mitchell, S. R., Gopakumar, J., Jaiswal, S. 2021; 66: 63–69

  Abstract

  In the multi-hit model of carcinogenesis, a precancerous state often precedes overt malignancy. Identification of these states has been of great interest as they allow for early identification of at-risk individuals before the appearance of a future cancer. One such condition has recently been described for blood cancers: Clonal Hematopoiesis of Indeterminate Potential (CHIP). Recent research advances have elucidated the risk of progression of CHIP to myeloid malignancies, its potential as a precursor for non-myeloid blood cancers, and its association with non-hematological cancers. Understanding the evolution of CHIP to hematological malignancy may help identify CHIP carriers at high risk of transformation and lead to the development of targeted therapies that can be deployed preemptively.

  View details for DOI 10.1016/j.gde.2020.12.004

  View details for PubMedID 33422951

• Association of Clonal Hematopoiesis with Chronic Obstructive Pulmonary Disease. Blood Miller, P., Qiao, D., Rojas-Quintero, J., Honigberg, M. C., Sperling, A. S., Gibson, C. J., Bick, A. G., Niroula, A., McConkey, M. E., Sandoval, B., Miller, B., Shi, W., Viswanathan, K., Leventhal, M. J., Werner, L., Moll, M., Cade, B., Barr, R. G., Correa, A., Cupples, L. A., Gharib, S. A., Jain, D., Gogarten, S., Lange, L., London, S., Manichaikul, A., O'Connor, G., Oelsner, E., Redline, S., Rich, S. S., Rotter, J. I., Ramachandran, V., Yu, B., Sholl, L. M., Neuberg, D., Jaiswal, S., Levy, B., Owen, C., Natarajan, P., Silverman, E. K., van Galen, P., Tesfaigzi, Y., Cho, M., Ebert, B. L. 2021

  Abstract

  Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association with COPD remains unclear. We analyzed whole-genome and exome sequencing data to detect CHIP in 48,835 subjects, of whom 8,444 had moderate-to-very-severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In COPDGene, individuals with CHIP had a risk of moderate-to-severe and severe or very severe COPD 1.6 and 2.2 times greater than non-carriers, respectively (adjusted 95% confidence intervals [CI], 1.1 to 2.2 and 1.5 to 3.2). These findings were consistent observed in three additional cohorts and meta-analyses of all subjects. CHIP was also associated with decreased FEV1% predicted in COPDGene (mean between group difference -5.7%; adjusted 95% CI, -8.8 to -2.6), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (OR 1.03 per ten pack-years, 95% CI 1.01-1.05) in the meta-analysis of all subjects. Inactivation of Tet2 in mouse hematopoietic cells exacerbated emphysema development and inflammation in cigarette smoke exposure models. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.

  View details for DOI 10.1182/blood.2021013531

  View details for PubMedID 34855941

• Preventive Cardio-Oncology: Cardiovascular Disease Prevention in Cancer Patients and Survivors CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE Iacopo, F., Branch, M., Cardinale, D., Middeldorp, M., Sanders, P., Cohen, J. B., Achirica, M., Jaiswal, S., Brown, S. 2021; 23 (1)

  View details for DOI 10.1007/s11936-020-00883-1

  View details for Web of Science ID 001000671400007

• Clonal hematopoiesis and nonhematologic disorders BLOOD Jaiswal, S. 2020; 136 (14): 1606–14

  Abstract

  Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal hematopoiesis is an increased risk of hematologic cancers, which has now been shown in several studies. However, the hematopoietic stem cells that acquire these somatic mutations also give rise to mutated immune effector cells, such as monocytes, granulocytes, and lymphocytes. These effector cells can potentially influence many disease states, especially those with a chronic inflammatory component. Indeed, several studies have now shown that clonal hematopoiesis associates with increased risk of atherosclerotic cardiovascular disease. Emerging data also associate clonal hematopoiesis with other nonhematologic diseases. Here, we will review recent studies linking clonal hematopoiesis to altered immune function, inflammation, and nonmalignant diseases of aging.

  View details for DOI 10.1182/blood.2019000989

  View details for Web of Science ID 000579872400011

  View details for PubMedID 32736379

• Genetic regulation of gene expression and splicing during a 10-year period of human aging. Genome biology Balliu, B., Durrant, M., Goede, O. d., Abell, N., Li, X., Liu, B., Gloudemans, M. J., Cook, N. L., Smith, K. S., Knowles, D. A., Pala, M., Cucca, F., Schlessinger, D., Jaiswal, S., Sabatti, C., Lind, L., Ingelsson, E., Montgomery, S. B. 2019; 20 (1): 230

  Abstract

  BACKGROUND: Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age.RESULTS: We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age.CONCLUSIONS: These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.

  View details for DOI 10.1186/s13059-019-1840-y

  View details for PubMedID 31684996

• Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nature reviews. Cardiology Jaiswal, S., Libby, P. 2019

  Abstract

  Ageing and inflammation strongly drive the risk of cardiovascular disease. Work over the past decade has uncovered a common condition characterized by the positive selection of certain somatic mutations in haematopoietic stem cells in ageing humans. This phenomenon, known as clonal haematopoiesis of indeterminate potential (CHIP), occurs most commonly as a result of mutations in the transcriptional regulators DNMT3A, TET2 and ASXL1. CHIP is associated with a variety of adverse outcomes, including haematological cancer and death. Surprisingly, CHIP is also associated with a doubling of the risk of atherosclerotic cardiovascular disease. Studies in mice support the causality of this relationship. Mutations in TET2, which are among the most commonly found mutations in CHIP, lead to increased expression of inflammatory genes in innate immune cells, potentially explaining the link between mutations and increased cardiovascular risk. Therapies targeting the mutant clones or the increased inflammatory mediators might be useful for ameliorating the risk of cardiovascular disease. We propose that the mutations leading to clonal haematopoiesis contribute to the increased inflammation seen in ageing and thereby explain some of the age-related risk of cardiovascular disease.

  View details for DOI 10.1038/s41569-019-0247-5

  View details for PubMedID 31406340

• It's in the blood. Nature medicine Jaiswal, S. 2019; 25 (8): 1184

  View details for DOI 10.1038/s41591-019-0537-9

  View details for PubMedID 31388172

• Clonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD JACC Review Topic of the Week JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Khetarpal, S. A., Qamar, A., Bick, A. G., Fuster, J. J., Kathiresan, S., Jaiswal, S., Natarajan, P. 2019; 74 (4): 578–86

  Abstract

  The incidence of cardiovascular diseases increases with age and is also correlated with increased inflammatory burden. Recently, human genetics provided a new paradigm linking aging, inflammation, and atherosclerotic cardiovascular disease (ASCVD). Next-generation genetic sequencing of whole blood-derived DNA in humans showed that clonal expansion of hematopoietic cells with somatic mutations in leukemogenic genes was associated with age and correlated with increased mortality. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), was associated with hematologic malignancy as well as ASCVD independently of age and other traditional risk factors. Because the implication of CHIP with ASCVD, genetic loss-of-function studies of Tet2 and Dnmt3a in murine models have supported a mechanistic role for CHIP in promoting vascular disease. Despite the potential contribution of CHIP to myriad cardiovascular and aging-related diseases, the epidemiology and biology surrounding this phenomenon remains incompletely appreciated and understood, especially as applied to clinical practice and prognostication. Here, the authors review this emerging key risk factor, defining its discovery, relationship to cardiovascular diseases, preclinical evidence for causality, and implications for risk prediction and mitigation.

  View details for DOI 10.1016/j.jacc.2019.05.045

  View details for Web of Science ID 000476594000013

  View details for PubMedID 31345433

  View details for PubMedCentralID PMC6662618

• Clonal Hematopoiesis Crossroads of Aging, Cardiovascular Disease, and Cancer: JACC Review Topic of the Week JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Libby, P., Sidlow, R., Lin, A. E., Gupta, D., Jones, L. W., Moslehi, J., Zeiher, A., Jaiswal, S., Schulz, C., Blankstein, R., Bolton, K. L., Steensma, D., Levine, R. L., Ebert, B. L. 2019; 74 (4): 567–77

  Abstract

  A novel, common, and potent cardiovascular risk factor has recently emerged: clonal hematopoiesis of indeterminate potential (CHIP). CHIP arises from somatic mutations in hematopoietic stem cells that yield clonal progeny of mutant leukocytes in blood. Individuals with CHIP have a doubled risk of coronary heart disease and ischemic stroke, and worsened heart failure outcomes independent of traditional cardiovascular risk factors. The recognition of CHIP as a nontraditional risk factor challenges specialists in hematology/oncology and cardiovascular medicine alike. Should we screen for CHIP? If so, in whom? How should we assess cardiovascular risk in people with CHIP? How should we manage the excess cardiovascular risk in the absence of an evidence base? This review explains CHIP, explores the clinical quandaries, strives to provide reasonable recommendations for the multidisciplinary management of cardiovascular risk in individuals with CHIP, and highlights current knowledge gaps.

  View details for DOI 10.1016/j.jacc.2019.06.007

  View details for Web of Science ID 000476594000012

  View details for PubMedID 31345432

  View details for PubMedCentralID PMC6681657

• Connections Between Clonal Hematopoiesis, Cardiovascular Disease, and Cancer: A Review. JAMA cardiology Calvillo-Arguelles, O., Jaiswal, S., Shlush, L. I., Moslehi, J. J., Schimmer, A., Barac, A., Thavendiranathan, P. 2019

  Abstract

  Importance: Clonal hematopoiesis (CH) has been recently described as a novel driver for cancer and cardiovascular disease (CVD). Clonal hematopoiesis is a common, age-associated disorder marked by expansion of hematopoietic clones carrying recurrent somatic mutations. Current literature suggests that patients with CH have a higher risk of subsequent hematological malignant conditions and mortality attributable to excess CVD. This review discusses the association of cancer with CVD with CH as a potential unifying factor.Observations: The prevalence of CH varies based on the sequencing depth, diagnostic criteria, and patient age and ranges from less than 1% in those younger than 40 years to more than 15% to 20% in those 90 years and older. Clonal hematopoiesis is associated with a 0.5% to 1.0% absolute annual risk of hematological malignant condition and a 2-fold to 4-fold higher risk of coronary artery disease, stroke, and CVD deaths, independent of traditional cardiovascular risk factors. In fact, CH appears to have a relative risk similar to that of traditional cardiovascular risk factors for CVD. Experimental studies suggest that the link between CVD and CH is causal, with inflammation as 1 potential mechanism. There may be also a link between CH and CVD in survivors of cancer; however, data to support this association are currently limited.Conclusions and Relevance: Clonal hematopoiesis represents a premalignant state, with carriers having an increased risk of hematological malignant conditions. Although most carriers will not develop a malignant condition, CH confers an increased risk of CVD, possibly via inflammation. Clonal hematopoiesis may also contribute to CVD in survivors of cancer, although this hypothesis requires validation. Clinically, as advanced sequencing techniques become available, CH may pave the way for precision medicine in the field of cardio-oncology.

  View details for PubMedID 30865214

• Clonal hematopoiesis: Pre-cancer PLUS. Advances in cancer research Silver, A. J., Jaiswal, S. 2019; 141: 85–128

  Abstract

  Clonal hematopoiesis is a common, age-related process in which a somatically mutated hematopoietic precursor gives rise to a genetically distinct subpopulation in the blood. This phenomenon has been observed in populations across the globe and, while virtually non-existent in children is estimated to affect >10% of the 70-and-older age group. The mutations are thought to occur in stem cells, which makes them pre-cancerous, and precursors to cancer stem cells. Many of the genes most commonly mutated in clonal hematopoiesis are also recurrently mutated in leukemia, genes such as DNMT3A, TET2, ASXL1, JAK2, and TP53. However, between 40% and 60% of cases arise from the accumulation of what appear to be random mutations outside of known driver genes. Clonal hematopoiesis is frequently present in otherwise healthy individuals and may persist for many years. Though largely asymptomatic, carrying these somatic mutations confers a small but significantly increased risk of leukemic transformation, affecting 0.5-1% carriers per year; although most genes confer an increased risk of transformation, mutations in TP53 and U2AF1 appear to carry a particularly high risk for transformation. Additionally, a patient's history of prior treatment with cytotoxic chemotherapy and/or radiation are correlated with the development of clonal hematopoiesis; in the setting of chemotherapy treatment of solid tumors, hematopoietic mutations in TP53 and PPM1D appear to contribute to outgrowth of clones that may lead to subsequent malignancy. The presence of a clone also imparts a significantly increased risk of cardiovascular disease, which in some cases appears to be due to increased inflammation and atherosclerosis. Clonal hematopoiesis is correlated with several other diseases as well, including diabetes, chronic pulmonary disease, and aplastic anemia, with other associations probably yet to be uncovered.

  View details for PubMedID 30691686

• Biological implications of clonal hematopoiesis. Experimental hematology Luis, T. C., Wilkinson, A. C., Beerman, I. n., Jaiswal, S. n., Shlush, L. I. 2019

  Abstract

  Adult hematological malignancies, such as acute myeloid leukemia, are thought to arise through the gradual acquisition of oncogenic mutations within long-lived hematopoietic stem cells (HSCs). Genomic analysis of peripheral blood DNA has recently identified leukemia-associated genetic mutations within otherwise healthy individuals, an observation that is strongly associated with age. These genetic mutations are often found at high frequency, suggesting dominance of a mutant HSC clone. Expansion of clones carrying other mutations not associated with leukemia or larger chromosomal deletions were also observed. This clinical observation has been termed clonal hematopoiesis, a condition associated with increased the risk of both hematological malignancy and cardiovascular disease. Here, we discuss the identification of clonal hematopoiesis and its implications on human health, based on the May 2019 International Society for Experimental Hematology New Investigator Committee Webinar.

  View details for DOI 10.1016/j.exphem.2019.08.004

  View details for PubMedID 31472170

• CHIPping Away at the Pathogenesis of Heart Failure JAMA CARDIOLOGY Libby, P., Jaiswal, S., Lin, A. E., Ebert, B. L. 2019; 4 (1): 5–6

  View details for DOI 10.1001/jamacardio.2018.4039

  View details for Web of Science ID 000456041500001

• Loss-of-Function Mutations in Dnmt3a and Tet2 Lead to Accelerated Atherosclerosis and Convergent Macrophage Phenotypes in Mice Rauch, P. J., Silver, A. J., Gopakumar, J., McConkey, M., Sinha, E., Fefer, M., Shvartz, E., Sukhova, G., Libby, P., Ebert, B. L., Jaiswal, S. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-118288

  View details for Web of Science ID 000454837602123

• Predicting progression to AML NATURE MEDICINE Sellar, R. S., Jaiswal, S., Ebert, B. L. 2018; 24 (7): 904–6

  View details for PubMedID 29988142

• Clonal Hematopoiesis Somatic Mutations in Blood Cells and Atherosclerosis CIRCULATION-GENOMIC AND PRECISION MEDICINE Natarajan, P., Jaiswal, S., Kathiresan, S. 2018; 11 (7): e001926

  Abstract

  The most important prognostic factor for atherosclerotic cardiovascular disease is age, independent of all other recognized risk factors. Recently, exome sequence analyses showed that somatic mutations in blood cells, a process termed clonal hematopoiesis, are common and increase in prevalence with age, with at least 1 in 10 adults older than 70 years affected. Carriers of clonal hematopoiesis have been shown to be not only at heightened risk for hematologic malignancy but also at increased risk for atherosclerotic cardiovascular disease. Here, we review the prior literature of clonal selection and expansion of hematopoietic stem cells and the evidence supporting its causal association with atherosclerotic cardiovascular disease.

  View details for PubMedID 29987111

• Clonal Hematopoiesis and Atherosclerosis. The New England journal of medicine Jaiswal, S., Natarajan, P., Ebert, B. L. 2017; 377 (14): 1401-1402

  View details for DOI 10.1056/NEJMc1710381

  View details for PubMedID 28976867

• Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma JOURNAL OF CLINICAL ONCOLOGY Gibson, C. J., Lindsley, R. C., Tchekmedyian, V., Mar, B. G., Shi, J., Jaiswal, S., Bosworth, A., Francisco, L., He, J., Bansal, A., Morgan, E. A., LaCasce, A. S., Freedman, A. S., Fisher, D. C., Jacobsen, E., Armand, P., Alyea, E. P., Koreth, J., Ho, V., Soiffer, R. J., Antin, J. H., Ritz, J., Nikiforow, S., Forman, S. J., Michor, F., Neuberg, D., Bhatia, R., Bhatia, S., Ebert, B. L. 2017; 35 (14): 1598-?

  Abstract

  Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes. Methods We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010. We assessed the effect of CHIP at the time of ASCT on subsequent outcomes, including TMN, cause-specific mortality, and overall survival. Results For six of 12 patients in the exome sequencing cohort, mutations found in the TMN specimen were also detectable in the pre-ASCT specimen. In the targeted sequencing cohort, 120 patients (29.9%) had CHIP at the time of ASCT, which was associated with an increased rate of TMN (10-year cumulative incidence, 14.1% v 4.3% for those with and without CHIP, respectively; P = .002). Patients with CHIP had significantly inferior overall survival compared with those without CHIP (10-year overall survival, 30.4% v 60.9%, respectively; P < .001), including increased risk of death from TMN and cardiovascular disease. Conclusion In patients undergoing ASCT for lymphoma, CHIP at the time of transplantation is associated with inferior survival and increased risk of TMN.

  View details for DOI 10.1200/JCO.2016.71.6712

  View details for Web of Science ID 000400811200016

  View details for PubMedID 28068180

  View details for PubMedCentralID PMC5455707

• Clonal hematopoiesis SEMINARS IN HEMATOLOGY Jan, M., Ebert, B. L., Jaiswal, S. 2017; 54 (1): 43-50

  Abstract

  Cancer results from multistep pathogenesis, yet the pre-malignant states that precede the development of many hematologic malignancies have been difficult to identify. Recent genomic studies of blood DNA from tens of thousands of people have revealed the presence of remarkably common, age-associated somatic mutations in genes associated with hematologic malignancies. These somatic mutations drive the expansion from a single founding cell to a detectable hematopoietic clone. Owing to the admixed nature of blood that provides a sampling of blood cell production throughout the body, clonal hematopoiesis is a rare view into the biology of pre-malignancy and the direct effects of pre-cancerous lesions on organ dysfunction. Indeed, clonal hematopoiesis is associated not only with increased risk of hematologic malignancy, but also with cardiovascular disease and overall mortality. Here we review rapid advances in the genetic understanding of clonal hematopoiesis and nascent evidence implicating clonal hematopoiesis in malignant and non-malignant age-related disease.

  View details for DOI 10.1053/j.seminhematol.2016.10.002

  View details for Web of Science ID 000393445800008

  View details for PubMedID 28088988

• Clonal Hematopoiesis and Blood-Cancer Risk NEW ENGLAND JOURNAL OF MEDICINE Yan, B., Ban, K., Chng, W. 2015; 372 (11): 1071-1071

  View details for DOI 10.1056/NEJMc1500684

  View details for Web of Science ID 000350797300014

  View details for PubMedID 25760362

• Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance NATURE MEDICINE Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S., Kim, S. S., Liu, H., Tivey, T., Christie, A. L., Elpek, K. G., Card, J., Gritsman, K., Gotlib, J., Deininger, M. W., Makishima, H., Turley, S. J., Javidi-Sharifi, N., Maciejewski, J. P., Jaiswal, S., Ebert, B. L., Rodig, S. J., Tyner, J. W., Marto, J. A., Weinstock, D. M., Lane, A. A. 2015; 21 (1): 71-75

  Abstract

  Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.

  View details for DOI 10.1038/nm.3751

  View details for PubMedID 25485910

• MDS Is a Stem Cell Disorder After All CANCER CELL Jaiswal, S., Ebert, B. L. 2014; 25 (6): 713-714

  Abstract

  Myelodysplastic syndrome (MDS) has long been presumed to be a stem cell disorder, but rigorous formal proof has been lacking. In this issue of Cancer Cell, Woll and colleagues demonstrate that driver mutations occurring in MDS definitively occur in cells with a stem cell phenotype.

  View details for DOI 10.1016/j.ccr.2014.06.001

  View details for Web of Science ID 000337709600002

  View details for PubMedID 24937455

• Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice JOURNAL OF EXPERIMENTAL MEDICINE Han, M. H., Lundgren, D. H., Jaiswal, S., Chao, M., Graham, K. L., Garris, C. S., Axtell, R. C., Ho, P. P., Lock, C. B., Woodard, J. I., Brownell, S. E., Zoudilova, M., Hunt, J. F., Baranzini, S. E., Butcher, E. C., Raine, C. S., Sobel, R. A., Han, D. K., Weissman, I., Steinman, L. 2012; 209 (7): 1325-1334

  Abstract

  Comparison of transcriptomic and proteomic data from pathologically similar multiple sclerosis (MS) lesions reveals down-regulation of CD47 at the messenger RNA level and low abundance at the protein level. Immunohistochemical studies demonstrate that CD47 is expressed in normal myelin and in foamy macrophages and reactive astrocytes within active MS lesions. We demonstrate that CD47(-/-) mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen. In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system. In vitro assays demonstrate that blocking CD47 also promotes phagocytosis of myelin and that this effect is dependent on signal regulatory protein α (SIRP-α). Immune regulation and phagocytosis are mechanisms for CD47 signaling in autoimmune neuroinflammation. Depending on the cell type, location, and disease stage, CD47 has Janus-like roles, with opposing effects on EAE pathogenesis.

  View details for DOI 10.1084/jem.20101974

  View details for Web of Science ID 000306174300008

  View details for PubMedID 22734047

  View details for PubMedCentralID PMC3405500

• The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Willingham, S. B., Volkmer, J., Gentles, A. J., Sahoo, D., Dalerba, P., Mitra, S. S., Wang, J., Contreras-Trujillo, H., Martin, R., Cohen, J. D., Lovelace, P., Scheeren, F. A., Chao, M. P., Weiskopf, K., Tang, C., Volkmer, A. K., Naik, T. J., Storm, T. A., Mosley, A. R., Edris, B., Schmid, S. M., Sun, C. K., Chua, M., Murillo, O., Rajendran, P., Cha, A. C., Chin, R. K., Kim, D., Adorno, M., Raveh, T., Tseng, D., Jaiswal, S., Enger, P. O., Steinberg, G. K., Li, G., So, S. K., Majeti, R., Harsh, G. R., van de Rijn, M., Teng, N. N., Sunwoo, J. B., Alizadeh, A. A., Clarke, M. F., Weissman, I. L. 2012; 109 (17): 6662-6667

  Abstract

  CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

  View details for DOI 10.1073/pnas.1121623109

  View details for PubMedID 22451913

• Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by CD47 SCIENCE TRANSLATIONAL MEDICINE Chao, M. P., Jaiswal, S., Weissman-Tsukamoto, R., Alizadeh, A. A., Gentles, A. J., Volkmer, J., Weiskopf, K., Willingham, S. B., Raveh, T., Park, C. Y., Majeti, R., Weissman, I. L. 2010; 2 (63)

  Abstract

  Under normal physiological conditions, cellular homeostasis is partly regulated by a balance of pro- and anti-phagocytic signals. CD47, which prevents cancer cell phagocytosis by the innate immune system, is highly expressed on several human cancers including acute myeloid leukemia, non-Hodgkin's lymphoma, and bladder cancer. Blocking CD47 with a monoclonal antibody results in phagocytosis of cancer cells and leads to in vivo tumor elimination, yet normal cells remain mostly unaffected. Thus, we postulated that cancer cells must also display a potent pro-phagocytic signal. Here, we identified calreticulin as a pro-phagocytic signal that was highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells. Increased CD47 expression correlated with high amounts of calreticulin on cancer cells and was necessary for protection from calreticulin-mediated phagocytosis. Blocking the interaction of target cell calreticulin with its receptor, low-density lipoprotein receptor-related protein, on phagocytic cells prevented anti-CD47 antibody-mediated phagocytosis. Furthermore, increased calreticulin expression was an adverse prognostic factor in diverse tumors including neuroblastoma, bladder cancer, and non-Hodgkin's lymphoma. These findings identify calreticulin as the dominant pro-phagocytic signal on several human cancers, provide an explanation for the selective targeting of tumor cells by anti-CD47 antibody, and highlight the balance between pro- and anti-phagocytic signals in the immune evasion of cancer.

  View details for DOI 10.1126/scitranslmed.3001375

  View details for Web of Science ID 000288444900003

  View details for PubMedID 21178137

• Macrophages as mediators of tumor immunosurveillance TRENDS IN IMMUNOLOGY Jaiswal, S., Chao, M. P., Majeti, R., Weissman, I. L. 2010; 31 (6): 212-219

  Abstract

  Tumor immunosurveillance is a well-established mechanism for regulation of tumor growth. In this regard, most studies have focused on the role of T- and NK-cells as the critical immune effector cells. However, macrophages play a major role in the recognition and clearance of foreign, aged, and damaged cells. Macrophage phagocytosis is negatively regulated via the receptor SIRPalpha upon binding to CD47, a ubiquitously expressed protein. We recently showed that CD47 is up-regulated in myeloid leukemia and migrating hematopoietic progenitors, and that the level of protein expression correlates with the ability to evade phagocytosis. These results implicate macrophages in the immunosurveillance of hematopoietic cells and leukemias. The ability of macrophages to phagocytose tumor cells might be exploited therapeutically by blocking the CD47-SIRPalpha interaction.

  View details for DOI 10.1016/j.it.2010.04.001

  View details for Web of Science ID 000279427000002

  View details for PubMedID 20452821

  View details for PubMedCentralID PMC3646798

• CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem Cells CELL Majeti, R., Chao, M. P., Alizadeh, A. A., Pang, W. W., Jaiswal, S., Gibbs, K. D., van Rooijen, N., Weissman, I. L. 2009; 138 (2): 286-299

  Abstract

  Acute myeloid leukemia (AML) is organized as a cellular hierarchy initiated and maintained by a subset of self-renewing leukemia stem cells (LSC). We hypothesized that increased CD47 expression on human AML LSC contributes to pathogenesis by inhibiting their phagocytosis through the interaction of CD47 with an inhibitory receptor on phagocytes. We found that CD47 was more highly expressed on AML LSC than their normal counterparts, and that increased CD47 expression predicted worse overall survival in three independent cohorts of adult AML patients. Furthermore, blocking monoclonal antibodies directed against CD47 preferentially enabled phagocytosis of AML LSC and inhibited their engraftment in vivo. Finally, treatment of human AML LSC-engrafted mice with anti-CD47 antibody depleted AML and targeted AML LSC. In summary, increased CD47 expression is an independent, poor prognostic factor that can be targeted on human AML stem cells with blocking monoclonal antibodies capable of enabling phagocytosis of LSC.

  View details for DOI 10.1016/j.cell.2009.05.045

  View details for PubMedID 19632179

• Hematopoietic Stem and Progenitor Cells and the Inflammatory Response 6th International Cancer Vaccine Symposium Jaiswal, S., Weissman, I. L. BLACKWELL PUBLISHING. 2009: 118–121

  Abstract

  Cells of the vertebrate immune system are continuously regenerated by division of hematopoietic stem cells (HSCs) into differentiated effector cells. Classically, HSCs were thought to reside primarily in the bone marrow niche where they produced mature progeny that migrated from the marrow to repopulate the peripheral immune system. However, emerging evidence has established that hematopoietic stem and progenitor cells (HSPCs) are themselves mobile and able to repopulate ectopic niches and contribute more directly to inflammatory responses in the periphery. How the HSPCs remain immune to destruction in a toxic inflammatory milieu is unknown.

  View details for Web of Science ID 000271828500015

  View details for PubMedID 19769744

• Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Jaiswal, S., Traver, D., Miyamoto, T., Akashi, K., Lagasse, E., Weissman, I. L. 2003; 100 (17): 10002-10007

  Abstract

  Chronic myelogenous leukemia is a myeloproliferative disorder (MPD) that, over time, progresses to acute leukemia. Both processes are closely associated with the t(9;22) chromosomal translocation that creates the BCR/ABL fusion gene in hematopoietic stem cells (HSCs) and their progeny. Chronic myelogenous leukemia is therefore classified as an HSC disorder in which a clone of multipotent HSCs is likely to be malignantly transformed, although direct evidence for malignant t(9;22)+ HSCs is lacking. To test whether HSC malignancy is required, we generated hMRP8p210BCR/ABL transgenic mice in which expression of BCR/ABL is absent in HSCs and targeted exclusively to myeloid progenitors and their myelomonocytic progeny. Four of 13 BCR/ABL transgenic founders developed a chronic MPD, but only one progressed to blast crisis. To address whether additional oncogenic events are required for progression to acute disease, we crossed hMRP8p210BCR/ABL mice to apoptosis-resistant hMRP8BCL-2 mice. Of 18 double-transgenic animals, 9 developed acute myeloid leukemias that were transplantable to wild-type recipients. Taken together, these data indicate that a MPD can arise in mice without expression of BCR/ABL in HSCs and that additional mutations inhibiting programmed cell death may be critical in the transition of this disease to blast-crisis leukemia.

  View details for DOI 10.1073/pnas.1633833100

  View details for Web of Science ID 000184926000069

  View details for PubMedID 12890867

  View details for PubMedCentralID PMC187741