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
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)
Doctor of Philosophy, The University of Tokyo (2014)
Doctor of Medicine, Asahikawa Medical College (2005)
Ravindra Majeti, Postdoctoral Faculty Sponsor
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 the lives of patients. 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 PhD 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 current postdoctoral fellowship in the laboratory of Professor Ravindra Majeti, Department of Hematology at Stanford University.
Many people suffer from leukemia each year, but we still don’t know how to completely cure it. Recent advances in sequencing technologies have tremendously improved our understanding of the underlying mutations that drive hematologic malignancies, although, the reality is that the majority of the mutations are not easily “druggable” and the discovery of these mutations has not yet made a significant impact in patient outcomes. I view this perhaps the most crucial challenges facing a translational cancer researcher like myself. My current research is a major step toward my long term goal to make personalized medicine a reality for patients with acute myeloid leukemia (AML) and other hematologic malignancies. Although my research is focused on targeting Ten-Eleven Translocation methylcytosine dioxygenase-2 (TET2) mutations, I anticipate it will lead to a better understanding of the cell context requirement for TET2 mutations in AML and help identify the critical cells to target to both prevent the development of de novo leukemia and halt relapse. It may also prove of value to understanding of the biology of a range of other cancers.
- Azacitidine and Ascorbate Inhibit the Competitive Outgrowth of Human TET2 Mutant HSPCs in a Xenograft Model of Pre-Leukemia AMER SOC HEMATOLOGY. 2018
- Hematopoietic Stem Cells Harrison's Principles of Internal Medicine (Japanese 5th Edition) MEDSI. 2017; 19: 89e1-4
Effective treatment against severe graft-versus-host disease with allele-specific anti-HLA monoclonal antibody in a humanized mouse model.
2015; 43 (2): 79-88 e1 4
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
2010; 92 (1): 179-185
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
Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2.
The Journal of clinical investigation
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.
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
- An Engineered Cell-Traceable Model of Reticular Dysgenesis in Human Hematopoietic Stem Cells Linking Metabolism and Differentiation 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 AMER SOC HEMATOLOGY. 2018
Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment.
Cell stem cell
2018; 22 (4): 600–607.e4
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
Establishment of a Therapeutic Anti-Pan HLA-Class II Monoclonal Antibody That Directly Induces Lymphoma Cell Death via Large Pore Formation.
2016; 11 (3): e0150496
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
2015; 5 (4): 597-608
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