Bio


My research projects aim to investigate the biology of human leukemia. I believe my research will contribute to clarify the disease pathogenesis of leukemia and help identify the critical cells to target to both prevent the development of de novo leukemia and halt relapse.

Honors & Awards


  • Allele-specific anti-HLA antibodies as theranostic agents in hematopoietic cell transplantation, SPARK (2023)
  • 60th ASH Abstract Achievement Award (Oral Presentation), American Society of Hematology (2018)
  • Stanford University School of Medicine, the Dean's Postdoctoral Fellowship, Stanford University (2016)
  • Overseas Award, Nakayama Foundation for Human Science (2014)

Boards, Advisory Committees, Professional Organizations


  • Associate Member, The American Association for Cancer Research (2015 - Present)
  • Associate Member, The American Society of Hematology (2015 - Present)
  • Member, The Japanese Society for Immunology (2011 - Present)
  • Member, The Japanese Society of Hematology (2006 - Present)
  • Member, The Japanese Society of Internal Medicine (2006 - Present)

Professional Education


  • Doctor of Medicine, Asahikawa Medical University, Medicine (2005)
  • Doctor of Philosophy, The University of Tokyo, Medicine (Pathology/ Immunology/Microbiology) (2014)

Current Research and Scholarly Interests


From 2005 to 2010, my work as a clinical hematology fellow allowed me to experience first-hand how scientific advances that started in a laboratory can transform patients' lives. While many of my patients were cured of their disease with allogeneic hematopoietic stem cell transplantation, underscoring the importance of anti-tumor immunotherapy in eradicating leukemia, I witnessed face-to-face their suffering from the long-term consequence of graft-versus-host disease (GVHD). This experience was ultimately what drove me to engage in research to discover novel therapies. For this reason, I embarked on a Ph.D. program in 2010 to design antibody therapy to (i) target GVHD and (ii) target hematological malignancies. Under the mentorship of Professor Hiromitsu Nakauchi at the University of Tokyo, an international leader in hematopoiesis, I developed allele-specific anti-human leukocyte antigen (HLA) monoclonal antibodies for severe GVHD caused by HLA-mismatched hematopoietic stem cell transplantation (Nakauchi et al., Exp Hematol, 2015). This study was the first to find that anti-HLA antibodies can be used therapeutically against GVHD. That success gave me the motivation and confidence to further my research beyond targeting GVHD to targeting leukemic stem cells through my postdoctoral fellowship in the laboratory of Professor Ravindra Majeti here at Stanford University.

Many people suffer from leukemia each year, but we still don't know how to cure it completely. Recent advances in sequencing technologies have tremendously improved our understanding of the underlying mutations that drive hematologic malignancies. However, the reality is that most of the mutations are not easily "druggable," and the discovery of these mutations has not yet significantly impacted patient outcomes. This is perhaps the most crucial challenge facing a translational cancer researcher like myself. My current research is a major step toward my long-term goal of making personalized medicine a reality for patients with acute myeloid leukemia (AML) and other hematologic malignancies.

Since joining the Majeti lab, I have been targeting the ten-eleven translocation methylcytosine dioxygenase-2 (TET2) mutation, which is aberrant in leukemia at a high rate and has been studied using human-derived cells. TET2 is known to be involved in the clonal expansion of cells, and people with this mutation are more likely to suffer from hematologic malignancies. It is also known to be involved in the development of coronary artery disease, a gene that has attracted much attention in recent studies. In my field, it is an essential gene involved in the abnormal proliferation of hematopoietic stem cells. Focusing on this gene, I mapped TET2-dependent 5hmC, epigenetic and transcriptional programs matched to competitive advantage, myeloid skewing, and reduced erythroid output in TET2-deficient hematopoietic stem and progenitor cells (HSPC). Vitamin C and azacitidine restore the 5hmC landscape and phenotypes in TET2-mutant HSPCs. These findings offer a comprehensive resource for TET-dependent transcriptional regulation of human hematopoiesis and shed light on the potential mechanisms by which TET deficiency contributes to clonal hematopoiesis and malignancies. Of course, these findings would also be of value in understanding the biology of normal hematopoietic stem cells (HSCs) and various other TET2-related cancers.

And from now on, I would like to use the single-cell transplantation techniques mastered in the Majeti lab to study the behavior of normal and aberrant human HSCs using various new methods, ultimately preventing the progression of AML.

In my clinical experience, I have lost many AML patients. With the regret and sadness of losing these patients in my heart, I hope to one day contribute to developing treatments that will fundamentally change how the world treats leukemia.

All Publications


  • Simplified Intrafemoral Injections Using Live Mice Allow for Continuous Bone Marrow Analysis Journal of Visualized Experiments Nakauchi, Y., Ediriwickrema, A., Martinez-Krams, D., Zhao, F., Rangavajhula, A., Karigane, D., Majeti, R. 2023

    Abstract

    Despite the complexity of hematopoietic cell transplantation in humans, researchers commonly perform intravenous or intrafemoral (IF) injections in mice. In murine models, this technique has been adapted to enhance the seeding efficiency of transplanted hematopoietic stem and progenitor cells (HSPCs). This paper describes a detailed step-by-step technical procedure of IF injection and the following bone marrow (BM) aspiration in mice that allows for serial characterization of cells present in the BM. This method enables the transplantation of valuable samples with low cell numbers that are particularly difficult to engraft by intravenous injection. This procedure facilitates the creation of xenografts that are critical for pathological analysis. While it is easier to access peripheral blood (PB), the cellular composition of PB does not reflect the BM, which is the niche for HSPCs. Therefore, procedures providing access to the BM compartment are essential for studying hematopoiesis. IF injection and serial BM aspiration, as described here, allow for the prospective retrieval and characterization of cells enriched in the BM, such as HSPCs, without sacrificing the mice.

    View details for DOI 10.3791/65874

  • Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability. Cancer discovery Thomas, D., Wu, M., Nakauchi, Y., Zheng, M., Thompson-Peach, C. A., Lim, K., Landberg, N., Kohnke, T., Robinson, N., Kaur, S., Kutyna, M., Stafford, M., Hiwase, D., Reinisch, A., Peltz, G., Majeti, R. 2022

    Abstract

    Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme (acetyl CoA carboxylase 1, ACC1) as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified a mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to beta-oxidation indicating reprogramming of metabolism towards a reliance on fatty acids. Compared to mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ HSPCs or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, not reversible by ivosidenib. Critically, pharmacologic targeting of ACC1 improved sensitivity of mIDH1 AML to venetoclax.

    View details for DOI 10.1158/2159-8290.CD-21-0218

    View details for PubMedID 36355448

  • The cell type specific 5hmC landscape and dynamics of healthy human hematopoiesis and TET2-mutant pre-leukemia. Blood cancer discovery Nakauchi, Y., Azizi, A., Thomas, D., Corces, M. R., Reinisch, A., Sharma, R., Cruz Hernandez, D., Kohnke, T., Karigane, D., Fan, A., Martinez-Krams, D., Stafford, M., Kaur, S., Dutta, R., Phan, P., Ediriwickrema, A., McCarthy, E., Ning, Y., Phillips, T., Ellison, C. K., Guler, G. D., Bergamaschi, A., Ku, C., Levy, S., Majeti, R. 2022

    Abstract

    The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that is mediated by ten-eleven-translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape of normal hematopoiesis and identify cell type-specific 5hmC profiles associated with active transcription and chromatin accessibility of key hematopoietic regulators. We utilized CRISPR/Cas9 to model TET2 loss-of-function mutations in primary human HSPCs. Disrupted cells exhibited increased colonies in serial replating, defective erythroid/megakaryocytic differentiation, and in vivo competitive advantage and myeloid skewing coupled with reduction of 5hmC at erythroid-associated gene loci. Azacitidine and ascorbate restored 5hmC abundance and slowed or reverted the expansion of TET2-mutant clones in vivo. These results demonstrate the key role of 5hmC in normal hematopoiesis and TET2-mutant phenotypes and raise the possibility of utilizing these agents to further our understanding of pre-leukemia/clonal hematopoiesis.

    View details for DOI 10.1158/2643-3230.BCD-21-0143

    View details for PubMedID 35532363

  • Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia. Nature cancer Zhang, H. n., Nakauchi, Y. n., Köhnke, T. n., Stafford, M. n., Bottomly, D. n., Thomas, R. n., Wilmot, B. n., McWeeney, S. K., Majeti, R. n., Tyner, J. W. 2020; 1 (8): 826–39

    Abstract

    Deregulation of the BCL2 gene family plays an important role in the pathogenesis of acute myeloid leukemia (AML). The BCL2 inhibitor, venetoclax, has received FDA approval for the treatment of AML. However, upfront and acquired drug resistance ensues due, in part, to the clinical and genetic heterogeneity of AML, highlighting the importance of identifying biomarkers to stratify patients onto the most effective therapies. By integrating clinical characteristics, exome and RNA sequencing, and inhibitor data from primary AML patient samples, we determined that myelomonocytic leukemia, upregulation of BCL2A1 and CLEC7A, as well as mutations of PTPN11 and KRAS conferred resistance to venetoclax and multiple venetoclax combinations. Venetoclax in combination with an MCL1 inhibitor AZD5991 induced synthetic lethality and circumvented venetoclax resistance.

    View details for DOI 10.1038/s43018-020-0103-x

    View details for PubMedID 33123685

    View details for PubMedCentralID PMC7591155

  • Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment. Cell stem cell Yamamoto, R. n., Wilkinson, A. C., Ooehara, J. n., Lan, X. n., Lai, C. Y., Nakauchi, Y. n., Pritchard, J. K., Nakauchi, H. n. 2018; 22 (4): 600–607.e4

    Abstract

    Aging is linked to functional deterioration and hematological diseases. The hematopoietic system is maintained by hematopoietic stem cells (HSCs), and dysfunction within the HSC compartment is thought to be a key mechanism underlying age-related hematopoietic perturbations. Using single-cell transplantation assays with five blood-lineage analysis, we previously identified myeloid-restricted repopulating progenitors (MyRPs) within the phenotypic HSC compartment in young mice. Here, we determined the age-related functional changes to the HSC compartment using over 400 single-cell transplantation assays. Notably, MyRP frequency increased dramatically with age, while multipotent HSCs expanded modestly within the bone marrow. We also identified a subset of functional cells that were myeloid restricted in primary recipients but displayed multipotent (five blood-lineage) output in secondary recipients. We have termed this cell type latent-HSCs, which appear exclusive to the aged HSC compartment. These results question the traditional dogma of HSC aging and our current approaches to assay and define HSCs.

    View details for PubMedID 29625072

  • Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse model. Experimental hematology Nakauchi, Y., Yamazaki, S., Napier, S. C., Usui, J., Ota, Y., Takahashi, S., Watanabe, N., Nakauchi, H. 2015; 43 (2): 79-88 e1 4

    Abstract

    Graft-versus-host disease (GVHD), mediated by donor-derived alloreactive T cells, is a major cause of non-relapse mortality in allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Its therapy is not well-defined. We established allele-specific anti-HLA monoclonal antibodies (ASHmAbs) that specifically target HLA molecules, with steady death of target-expressing cells. One such ASHmAb, against HLA-A*02:01 (A2-kASHmAb), was examined in a xenogeneic GVHD mouse model. To induce fatal GVHD, non-irradiated NOD/Shi-scid/IL-2Rγ(null) (NOG) mice were injected with healthy-donor human peripheral blood mononuclear cells (PBMCs), some expressing HLA-A*02:01, some not. Administration of A2-kASHmAb promoted the survival of mice injected with HLA-A*02:01-expressing PBMCs (p<0.0001) and, in humanized NOG mice, immediately cleared HLA-A*02:01-expressing human blood cells from mouse peripheral blood. Human PBMCs were again detectable in mouse blood 2-4 weeks after A2-kASHmAb administration, suggesting that kASHmAb may be safely administered to GVHD patients without permanently ablating the graft. This approach, different from those of existing GVHD pharmacotherapy, may open a new door for treatment of GVHD in HLA-mismatched allo-HSCT.

    View details for DOI 10.1016/j.exphem.2014.10.008

    View details for PubMedID 25448490

  • Concurrent administration of intravenous systemic and intravitreal methotrexate for intraocular lymphoma with central nervous system involvement INTERNATIONAL JOURNAL OF HEMATOLOGY Nakauchi, Y., Takase, H., Sugita, S., Mochizuki, M., Shibata, S., Ishiwata, Y., Shibuya, Y., Yasuhara, M., Miura, O., Arai, A. 2010; 92 (1): 179-185

    Abstract

    Intraocular lymphoma (IOL) is rare lymphoma that frequently infiltrates the central nervous system (CNS). An optimal treatment has not been established, and its prognosis is quite poor. We treated three IOL patients with CNS involvement by concurrent administration of intravenous and intravitreal methotrexate (MTX) injection. The intraocular lesion responded in all patients. One patient achieved complete response (CR), whereas the other 2 patients were in partial response for CNS lesion, added whole brain radiation and achieved CR. In 3 eyes of 2 patients, an intravitreal MTX injection (vMTX) was administered 2 h after a systemic MTX injection (sMTX) and the intravitreal MTX concentration was measured twice: 2 h after sMTX and 24 h after vMTX. The half-life of MTX in the vitreous fluid was estimated to be 12.4-21.5 h by assuming the first-order elimination kinetics. Although the concentration was still high 24 h after vMTX (69.94-82.89 muM), there were no ocular complications. The serum MTX concentration was not influenced by adding vMTX to sMTX. Grade 3 adverse event, leukocytopenia, was observed in only 1 patient. No grade 4 event was observed. Although further evaluation is required, concurrent sMTX and vMTX may be effective for IOL with CNS involvement.

    View details for DOI 10.1007/s12185-010-0589-6

    View details for Web of Science ID 000280578700024

    View details for PubMedID 20464643

  • IDH1-Mutant Preleukemic Hematopoietic Stem Cells Can Be Eliminated by Inhibition of Oxidative Phosphorylation. Blood cancer discovery Landberg, N., Köhnke, T., Feng, Y., Nakauchi, Y., Fan, A. C., Linde, M. H., Karigane, D., Lim, K., Sinha, R., Malcovati, L., Thomas, D., Majeti, R. 2024: OF1-OF18

    Abstract

    Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (AML) diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia.A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.

    View details for DOI 10.1158/2643-3230.BCD-23-0195

    View details for PubMedID 38261864

  • Genetically Corrected RAG2-SCID Human Hematopoietic Stem Cells Restore V(D)J-Recombinase and Rescue Lymphoid Deficiency. Blood advances Pavel-Dinu, M., Gardner, C. L., Nakauchi, Y., Kawai, T., Delmonte, O. M., Palterer, B., Bosticardo, M., Pala, F., Viel, S., Malech, H. L., Ghanim, H. Y., Bode, N. M., Kurgan, G. L., Detweiler, A. M., Vakulskas, C. A., Neff, N. F., Sheikali, A., Menezes, S. T., Chrobok, J., Hernandez Gonzalez, E. M., Majeti, R., Notarangelo, L. D., Porteus, M. H. 2023

    Abstract

    Recombination-activating genes (RAG1 and RAG2) are critical in lymphoid cell development and function by initiating the V(D)J-recombination process to generate polyclonal lymphocytes with broad antigen-specificity. Clinical manifestations of defective RAG1/2 genes range from immune dysregulation to severe combined immunodeficiencies (SCID), causing life-threatening infections and death early in life without hematopoietic cell transplantation (HCT). Despite improvements, haploidentical HCT without myeloablative conditioning carries a high risk of graft failure and incomplete immune reconstitution. The RAG complex is only expressed during the G0-G1 phases of the cell cycle at the early stages of T and B cell development, underscoring that a direct gene correction might capture the precise temporal expression of the endogenous gene. Here, we report a feasibility study using the CRISPR/Cas9-based "universal gene-correction" approach for the RAG2 locus in human hematopoietic stem/progenitor cells (HSPCs) from healthy donors and one RAG2-SCID patient. V(D)J recombinase activity was restored following gene correction of RAG2-SCID-derived HSPCs, resulting in the development of TCR ab and gd CD3+ cells and single-positive CD4+ and CD8+ lymphocytes. TCR repertoire analysis indicated a normal distribution of the CDR3 length and preserved usage of distal TRAV genes. We confirmed in vivo rescue of B-cell development, with normal IgM surface expression and a significant decrease in CD56bright NK cells. Together, we provide specificity, toxicity, and efficacy data supporting the development of a gene-correction therapy to benefit RAG2-deficient patients.

    View details for DOI 10.1182/bloodadvances.2023011766

    View details for PubMedID 38096800

  • IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation. Blood cancer discovery Landberg, N., Köhnke, T., Feng, Y., Nakauchi, Y., Fan, A. C., Linde, M. H., Karigane, D., Lim, K., Sinha, R., Malcovati, L., Thomas, D., Majeti, R. 2023

    Abstract

    Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC Class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent development and relapse of leukemia.

    View details for DOI 10.1158/2643-3230.BCD-23-0195

    View details for PubMedID 38091010

  • Simplified Intrafemoral Injections Using Live Mice Allow for Continuous Bone Marrow Analysis. Journal of visualized experiments : JoVE Nakauchi, Y., Ediriwickrema, A., Martinez-Krams, D., Zhao, F., Rangavajhula, A., Karigane, D., Majeti, R. 2023

    Abstract

    Despite the complexity of hematopoietic cell transplantation in humans, researchers commonly perform intravenous or intrafemoral (IF) injections in mice. In murine models, this technique has been adapted to enhance the seeding efficiency of transplanted hematopoietic stem and progenitor cells (HSPCs). This paper describes a detailed step-by-step technical procedure of IF injection and the following bone marrow (BM) aspiration in mice that allows for serial characterization of cells present in the BM. This method enables the transplantation of valuable samples with low cell numbers that are particularly difficult to engraft by intravenous injection. This procedure facilitates the creation of xenografts that are critical for pathological analysis. While it is easier to access peripheral blood (PB), the cellular composition of PB does not reflect the BM, which is the niche for HSPCs. Therefore, procedures providing access to the BM compartment are essential for studying hematopoiesis. IF injection and serial BM aspiration, as described here, allow for the prospective retrieval and characterization of cells enriched in the BM, such as HSPCs, without sacrificing the mice.

    View details for DOI 10.3791/65874

    View details for PubMedID 38009738

  • Engineering Sequential Mutations into Human HSPCs Yields an Aggressive Myeloid Malignancy Allowing for Interrogation of Preleukemic Transformation Collins, C. T., Nakauchi, Y., Koehnke, T., Chavez, J. S., Choi, S., Sharma, R., Zhao, F., Majeti, R. AMER SOC HEMATOLOGY. 2023
  • BCOR Loss Confers Increased Stemness and Partially Rescues RUNX1-Deficient Phenotypes in Human Hematopoietic Stem and Progenitor Cells Jackson, K. K., Fan, A. C., Karigane, D., Zhao, F., Collins, C. T., Nakauchi, Y., Kayamori, K., Rangavajhula, A. S., Koehnke, T., Majeti, R. AMER SOC HEMATOLOGY. 2023
  • Gene Correction of DNMT3A:R882H in Primary Human AML Demonstrates That This Mutation Is Not Required for Disease Maintenance, but Is Associated with Increased Leukemia Stem Cell Frequency Koehnke, T., Karigane, D., Hilgart, E., Kayamori, K., Fan, A. C., Collins, C. T., Suchy, F. P., Rangavajhula, A. S., Feng, Y., Nakauchi, Y., Martinez-Montes, E., Koldobskiy, M., Feinberg, A., Majeti, R. AMER SOC HEMATOLOGY. 2023
  • Intra-Leukemic IFN. Signaling Mediates Cell Cycle Suppression and Chemoresistance in AML Karigane, D., Fan, A. C., Kayamori, K., Nakauchi, Y., Koehnke, T., Rangavajhula, A. S., Ediriwickrema, A., Majeti, R. AMER SOC HEMATOLOGY. 2023
  • RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition. The Journal of clinical investigation Fan, A. C., Nakauchi, Y., Bai, L., Azizi, A., Nuno, K. A., Zhao, F., Köhnke, T., Karigane, D., Cruz-Hernandez, D., Reinisch, A., Khatri, P., Majeti, R. 2023

    Abstract

    Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we use primary patient samples and a RUNX1 knockout model in primary human hematopoietic cells to investigate how RUNX1 loss contributes to leukemic progression and to identify targetable vulnerabilities. Surprisingly, we found that RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the interleukin-3 (IL-3) receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1 KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable these aggressive blood cancers to be targeted with existing agents.

    View details for DOI 10.1172/JCI167053

    View details for PubMedID 37581927

  • Targeting IDH1-Mutated Pre-Leukemic Hematopoietic Stem Cells in Myeloid Disease, Including CCUS and AML Landberg, N., Koehnke, T., Nakauchi, Y., Fan, A., Karigane, D., Thomas, D., Majeti, R. AMER SOC HEMATOLOGY. 2022: 2234-2235
  • Reengineering Ponatinib to Minimize Cardiovascular Toxicity CANCER RESEARCH Hnatiuk, A. P., Bruyneel, A. N., Tailor, D., Pandrala, M., Dheeraj, A., Li, W., Serrano, R., Feyen, D. M., Vu, M. M., Amatya, P., Gupta, S., Nakauchi, Y., Morgado, I., Wiebking, V., Liao, R., Porteus, M. H., Majeti, R., Malhotra, S., Mercola, M. 2022; 82 (15): 2777-2791
  • IL-3 SELECTIVELY RESCUES RUNX1-DEFICIENT HUMAN HSPCS WITH DYSREGULATED JAK/ STAT SIGNALING Fan, A., Azizi, A., Nuno, K., Nakauchi, Y., Zhao, F., Cruz-Hernandez, D., Reinisch, A., Majeti, R. ELSEVIER SCIENCE INC. 2022: S84
  • IL-3 RESCUES PROLIFERATIVE DEFECTS IN INFLAMMATION-SENSITIVE RUNX1 DEFICIENT HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS Fan, A., Azizi, A., Dutta, R., Nakauchi, Y., Nuno, K., Zhao, F., Reinisch, A., Majeti, R. ELSEVIER SCIENCE INC. 2020: S59
  • Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2. The Journal of clinical investigation Dutta, R. n., Zhang, T. Y., Köhnke, T. n., Thomas, D. n., Linde, M. n., Gars, E. n., Stafford, M. n., Kaur, S. n., Nakauchi, Y. n., Yin, R. n., Azizi, A. n., Narla, A. n., Majeti, R. n. 2020

    Abstract

    Cancer-related anemia is present in over 60% of newly diagnosed cancer patients and is associated with substantial morbidity and high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates and improve quality of life. Clinical studies have observed an unexpected improvement in hemoglobin and red blood cell (RBC) transfusion-independence in AML patients treated with the isocitrate dehydrogenase 2 (IDH2) mutant-specific inhibitor, enasidenib, leading to improved quality of life without a reduction in AML disease burden. Here, we demonstrate that enasidenib enhanced human erythroid differentiation of hematopoietic progenitors. The phenomenon was not observed with other IDH1/2 inhibitors and occurred in IDH2-deficient CRIPSR-engineered progenitors independently of D-2-hydroxyglutarate. The effect of enasidenib on hematopoietic progenitors was mediated by protoporphyrin accumulation, driving heme production and erythroid differentiation in committed CD71+ progenitors rather than hematopoietic stem cells. Our results position enasidenib as a promising therapeutic agent for improvement of anemia and provide the basis for a clinical trial using enasidenib to decrease transfusion dependence in a wide array of clinical contexts.

    View details for DOI 10.1172/JCI133344

    View details for PubMedID 31895700

  • Use of polyvinyl alcohol for chimeric antigen receptor T-cell expansion. Experimental hematology Nishimura, T., Hsu, I., Martinez-Krams, D. C., Nakauchi, Y., Majeti, R., Yamazaki, S., Nakauchi, H., Wilkinson, A. C. 2019

    Abstract

    Serum albumin has long been an essential supplement for ex vivo hematopoietic and immune cell cultures. However, serum albumin medium supplements represent a major source of biological contamination in cell cultures and often cause loss of cellular function. As serum albumin exhibits significant batch-to-batch variability, it has also been blamed for causing major issues in experimental reproducibility. We recently discovered the synthetic polymer polyvinyl alcohol (PVA) as an inexpensive, Good Manufacturing Practice-compatible, and biologically inert serum albumin replacement for ex vivo hematopoietic stem cell cultures. Importantly, PVA is free of the biological contaminants that have plagued serum albumin-based media. Here, we describe that PVA can replace serum albumin in a range of blood and immune cell cultures including cell lines, primary leukemia samples, and human T lymphocytes. PVA can even replace human serum in the generation and expansion of functional chimeric antigen receptor (CAR) T cells, offering a potentially safer and more cost-efficient approach for this clinical cell therapy. In summary, PVA represents a chemically defined, biologically inert, and inexpensive alternative to serum albumin for a range of cell cultures in hematology and immunology.

    View details for DOI 10.1016/j.exphem.2019.11.007

    View details for PubMedID 31874780

  • Azacitidine and Ascorbate Inhibit the Competitive Outgrowth of Human TET2 Mutant HSPCs in a Xenograft Model of Pre-Leukemia Nakauchi, Y., Thomas, D., Sharma, R., Corces, M., Reinisch, A., Cruz, D., Koehnke, T., Karigane, D., Fan, A., Majeti, R. AMER SOC HEMATOLOGY. 2018
  • IDH1 Mutant AML Is Susceptible to Targeting De Novo Lipid Synthesis Independent of 2-Hydroxyglutarate and Has a Distinct Metabolic Profile from IDH2 Mutant AML Thomas, D., Nakauchi, Y., Wu, M., Zheng, M., Sinha, S., Dill, D., Peltz, G., Majeti, R. AMER SOC HEMATOLOGY. 2018
  • An Engineered Cell-Traceable Model of Reticular Dysgenesis in Human Hematopoietic Stem Cells Linking Metabolism and Differentiation Wang, W., Awani, A., Reich, L., Nakauchi, Y., Thomas, D., Dever, D. P., Porteus, M., Weinacht, K. G. AMER SOC HEMATOLOGY. 2018
  • Establishment of a Therapeutic Anti-Pan HLA-Class II Monoclonal Antibody That Directly Induces Lymphoma Cell Death via Large Pore Formation. PloS one Matsuoka, S., Ishii, Y., Nakao, A., Abe, M., Ohtsuji, N., Momose, S., Jin, H., Arase, H., Sugimoto, K., Nakauchi, Y., Masutani, H., Maeda, M., Yagita, H., Komatsu, N., Hino, O. 2016; 11 (3): e0150496

    Abstract

    To develop a new therapeutic monoclonal Antibody (mAb) for Hodgkin lymphoma (HL), we immunized a BALB/c mouse with live HL cell lines, alternating between two HL cell lines. After hybridization, we screened the hybridoma clones by assessing direct cytotoxicity against a HL cell line not used for immunization. We developed this strategy for establishing mAb to reduce the risk of obtaining clonotypic mAb specific for single HL cell line. A newly established mouse anti-human mAb (4713) triggered cytoskeleton-dependent, but complement- and caspase-independent, cell death in HL cell lines, Burkitt lymphoma cell lines, and advanced adult T-cell leukemia cell lines. Intravenous injection of mAb 4713 in tumor-bearing SCID mice improved survival significantly. mAb 4713 was revealed to be a mouse anti-human pan-HLA class II mAb. Treatment with this mAb induced the formation of large pores on the surface of target lymphoma cells within 30 min. This finding suggests that the cell death process induced by this anti-pan HLA-class II mAb may involve the same death signals stimulated by a cytolytic anti-pan MHC class I mAb that also induces large pore formation. This multifaceted study supports the therapeutic potential of mAb 4713 for various forms of lymphoma.

    View details for DOI 10.1371/journal.pone.0150496

    View details for PubMedID 27028595

  • A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy STEM CELL REPORTS Ando, M., Nishimura, T., Yamazaki, S., Yamaguchi, T., Kawana-Tachikawa, A., Hayama, T., Nakauchi, Y., Ando, J., Ota, Y., Takahashi, S., Nishimura, K., Ohtaka, M., Nakanishi, M., Miles, J. J., Burrows, S. R., Brenner, M. K., Nakauchi, H. 2015; 5 (4): 597-608

    Abstract

    The discovery of induced pluripotent stem cells (iPSCs) has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID) initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL) therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy.

    View details for DOI 10.1016/j.stemcr.2015.07.011

    View details for Web of Science ID 000364990900013

    View details for PubMedID 26321144