Dr. Jaiswal's lab focuses on understanding the biology of the aging hematopoietic system. As a post-doctoral fellow, he identified a common, pre-malignant state for blood cancers by reanalysis of large sequencing datasets. This condition, termed "clonal hematopoiesis", is characterized by the presence of stem cell clones harboring certain somatic mutations, primarily in genes involved in epigenetic regulation of hematopoiesis. Clonal hematopoiesis is prevalent in the aging population and increases the risk of not only blood cancer, but also cardiovascular disease and overall mortality. Understanding the biology of these mutations and how they contribute to the development of cancer and other age-related diseases is the current focus of work in the lab. These studies utilize genetic and clinical information from large population-based cohorts to understand the impact of clonal hematopoiesis in humans. The effect of the mutations causing clonal hematopoiesis is also studied in human and mouse tissues through a combination of genomic profiling, functional assays, and mouse models of disease.
- Transfusion Medicine
- Genomics and Molecular Pathology
- Clinical Pathology
Honors & Awards
New Innovator Award, National Institutes of Health (2020)
ASH Scholar Award, American Society of Hematology (2020)
EvansMDS Discovery Research Award, Evans Foundation (2018)
Transatlantic Network of Excellence, Foundation Leducq (2018)
Career Award for Medical Scientists, Burroughs Wellcome Fund (2016)
BroadIgnite Scholar, Broad Institute of MIT and Harvard (2016)
Paul E. Strandjord Young Investigator Award, ACLPS (2014)
Firestone Medal for Excellence in Research, Stanford University (2000)
Phi Beta Kappa, Stanford University (2000)
Medical Education: Stanford University School of Medicine (2010) CA
Board Certification: American Board of Pathology, Clinical Pathology (2017)
Fellowship, Harvard Medical School, Transfusion Medicine (2013)
Residency, Massachusetts General Hospital, Clinical Pathology (2014)
PhD, Stanford University School of Medicine, Immunology (2010)
MD, Stanford University School of Medicine (2010)
BS, Stanford University, Biological Sciences (2000)
Siddhartha Jaiswal, Irving L. Weissman, Ravindra Majeti, Mark P. Chao. "United States Patent 8562997 B2 Methods of treating acute myeloid leukemia by blocking CD47", The Board Of Trustees Of The Leland Stanford Junior University, Oct 22, 2013
Current Research and Scholarly Interests
Somatic Mutations in Aging
Aging is associated with an increased incidence of cancer and several other diseases. As a post-doctoral fellow, Dr. Jaiswal identified a common age-related disorder of the blood characterized by the acquisition of certain somatic mutations in hematopoietic stem cells (Jaiswal et al., NEJM 2014). These mutations allow stem cell clones to expand relative to normal stem cells; this clonal expansion is termed "clonal hematopoiesis of indeterminate potential", or CHIP (Steensma et al., Blood 2015).
The most commonly found mutations in CHIP are in genes involved in epigenetic regulation (DNMT3A, TET2, ASXL1). CHIP is very rare in the young, but becomes common with aging. Between 10-30% of the elderly have a clonal mutation meeting the definition of CHIP. Those with CHIP are at markedly increased risk of developing hematological malignancies such as myelodysplastic syndrome, acute myeloid leukemia, and lymphoma.
Surprisingly, CHIP is also associated with increased risk of atherosclerotic cardiovascular disease, and this relationship is thought to be causal based on mouse models (Jaiswal et al., NEJM 2017). Mechanistically, the mutations in CHIP lead to increased expression of inflammatory gene modules in mature immune cells such as macrophages. These immune effector cells are derived from the mutated hematopoietic stem cells in the marrow, hence they also harbor the CHIP-related mutations.
These observations suggest that somatic mutations in hematopoietic stem cells that arise during aging may have a variety of effects on health. The lab seeks to understand the biology and clinical impact of these mutations, as described in the projects below.
Using human population genetics to learn the health associations of clonal hematopoiesis.
Chronic inflammation seems to be a common feature of human aging, but the reasons for this are unclear. We hypothesize that CHIP might actually underlie much of the age-associated inflammation seen in humans. Consequently, CHIP might modulate the risk of several diseases of aging.
Mechanistic studies on the role of DNA methylation in clonal expansion of stem cells and dysregulated inflammation.
It is striking that the two most frequently mutated genes in CHIP, DNMT3A and TET2, are involved in DNA methylation dynamics. We hypothesize that these mutations lead to alterations in DNA methylation that promote self-renewal and inflammatory transcriptional programs. Using model systems, we will uncover the role of methylation in these programs.
Characterization of hematopoietic and immune cell subsets from humans with CHIP.
Much of our knowledge of the effects of mutations found in CHIP comes from mouse models because individuals with CHIP do not have overt disease, hence they do not enroll in clinical studies. We seek to prospectively identify individuals with CHIP to learn more about how these mutations affect stem cell and immune cell function in a native human context.
Identification of novel therapeutics to treat CHIP and/or its associated diseases.
If CHIP mutations lead to aberrant stem cell and immune cell function by altering gene expression, it should be possible to reverse these effects therapeutically. We aim to identify suitable targets for intervention to prevent stem cell expansion and inflammation associated with CHIP.
Graduate and Fellowship Programs
Clonal hematopoiesis in human aging and disease
2019; 366 (6465): 586-+
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
2018; 132 (11): 1095–1105
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
2017; 377 (2): 111-121
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
2015; 126 (1): 9-16
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
2014; 371 (26): 2488-2498
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
2009; 138 (2): 271-285
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
Genomic Profiling for Clinical Decision Making in Myeloid Neoplasms and Acute Leukemia.
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.
2022; 13 (1): 5350
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.
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
Longitudinal profiling of clonal hematopoiesis provides insight into clonal dynamics
IMMUNITY & AGEING
2022; 19 (1): 23
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.
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.
2022; 8 (14): eabl6579
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
2022; 3: 841796
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 2022; 6: 187-200
Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis.
The Journal of experimental medicine
2021; 218 (12)
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 AMER SOC HEMATOLOGY. 2021
- Clonal Hematopoiesis Is Driven By Aberrant Activation of TCL1A AMER SOC HEMATOLOGY. 2021
ZBTB33 is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing.
Blood cancer discovery
2021; 2 (5): 500-517
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
2021; 28 (8): 1335-1336
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.
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 2021; 591 (7851): E27
Insights into clonal hematopoiesis and its relation to cancer risk.
Current opinion in genetics & development
2021; 66: 63–69
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.
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
Clonal hematopoiesis and nonhematologic disorders
2020; 136 (14): 1606–14
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.
2019; 20 (1): 230
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
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 2019; 25 (8): 1184
Clonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD JACC Review Topic of the Week
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2019; 74 (4): 578–86
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
2019; 74 (4): 567–77
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.
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
2019; 141: 85–128
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.
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 2019; 4 (1): 5–6
- Loss-of-Function Mutations in Dnmt3a and Tet2 Lead to Accelerated Atherosclerosis and Convergent Macrophage Phenotypes in Mice AMER SOC HEMATOLOGY. 2018
Predicting progression to AML
2018; 24 (7): 904–6
View details for PubMedID 29988142
Clonal Hematopoiesis Somatic Mutations in Blood Cells and Atherosclerosis
CIRCULATION-GENOMIC AND PRECISION MEDICINE
2018; 11 (7): e001926
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 2017; 377 (14): 1401-1402
Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma
JOURNAL OF CLINICAL ONCOLOGY
2017; 35 (14): 1598-?
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
SEMINARS IN HEMATOLOGY
2017; 54 (1): 43-50
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 2015; 372 (11): 1071-1071
Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance
2015; 21 (1): 71-75
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
2014; 25 (6): 713-714
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
2012; 209 (7): 1325-1334
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
2012; 109 (17): 6662-6667
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
2010; 2 (63)
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
2010; 31 (6): 212-219
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
2009; 138 (2): 286-299
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
BLACKWELL PUBLISHING. 2009: 118–121
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
2003; 100 (17): 10002-10007
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