A5090254870- Acute Myeloid Leukemia Research
- Hematopoietic Stem Cell Transplantation
- Immune Cell Function and Interaction
- Chronic Lymphocytic Leukemia Research
- Cancer Genomics and Diagnostics
- CAR-T cell therapy research
- CRISPR and Genetic Engineering
- Cytokine Signaling Pathways and Interactions
- Protein Degradation and Inhibitors
- Blood disorders and treatments
- Epigenetics and DNA Methylation
- Histone Deacetylase Inhibitors Research
- T-cell and B-cell Immunology
- Cancer, Hypoxia, and Metabolism
- Chronic Myeloid Leukemia Treatments
- Acute Lymphoblastic Leukemia research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Lymphoma Diagnosis and Treatment
- RNA modifications and cancer
- GDF15 and Related Biomarkers
- Quinazolinone synthesis and applications
- Immune cells in cancer
- Hemoglobinopathies and Related Disorders
- Immunotherapy and Immune Responses
- Advanced Breast Cancer Therapies
Stanford University
2018-2025
California Institute for Regenerative Medicine
2018-2023
Cancer Institute (WIA)
2021-2023
Institute for Stem Cell Biology and Regenerative Medicine
2023
Stanford Cancer Institute
2018-2019
Cancer Prevention Institute of California
2018
The University of Tokyo
2011-2016
Tokyo University of Science
2014
Tokyo Medical and Dental University
2010
Aging is linked to functional deterioration and hematological diseases. The hematopoietic system maintained by stem cells (HSCs), dysfunction within the HSC compartment thought be a key mechanism underlying age-related perturbations. Using single-cell transplantation assays with five blood-lineage analysis, we previously identified myeloid-restricted repopulating progenitors (MyRPs) phenotypic in young mice. Here, determined changes using over 400 assays. Notably, MyRP frequency increased...
The discovery of induced pluripotent stem cells (iPSCs) has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential undifferentiated iPSCs is a major safety concern clinical translation. To address this issue, we demonstrated efficacy suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation iC9 with specific chemical inducer dimerization (CID) initiates caspase cascade that eliminates and tumors originated from We...
Abstract Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme [acetyl CoA carboxylase (ACC1)] as synthetic lethal target mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome primary acute myeloid leukemia (AML) blasts an mIDH1-specific reduction fatty acids. mIDH1 also induced switch to b-oxidation indicating reprogramming metabolism toward reliance on Compared...
The conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is a key step in DNA demethylation that mediated by ten-eleven translocation (TET) enzymes, which require ascorbate/vitamin C. Here, we report the 5hmC landscape normal hematopoiesis and identify cell type-specific profiles associated with active transcription chromatin accessibility hematopoietic regulators. We utilized CRISPR/Cas9 model TET2 loss-of-function mutations primary human stem progenitor cells (HSPC)....
A long-sought goal of cancer immunotherapy is to mass-produce T cells that specifically target tumor neoantigens. One decisive challenge the identification neoantigens derived from driver genes. Here, we identify recognize NSCLC-associated EGFR C797S mutation, which confers resistance current inhibitors and linked poor prognosis. To overcome limitations in cell availability, reprogrammed C797S-specific into induced pluripotent stem (iPSCs) re-differentiated them CD8⁺ cells. These...
In vivo gene therapy targeting hematopoietic stem cells (HSCs) holds significant therapeutic potential for treating hematological diseases. This study uses adeno-associated virus serotype 6 (AAV6) vectors and Cre recombination to systematically optimize the parameters effective in HSC transduction. We evaluated various genetic architectures delivery methods of AAV6, establishing an optimized protocol that achieved functional more than two-thirds immunophenotypic HSCs. Our findings highlight...
Abstract Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at time of acute myeloid leukemia (AML) diagnosis. pHSCs are origin and a potential reservoir for relapse. Using primary human samples gene editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, metabolic differences between healthy (HSC). We confirm that IDH1-driven clonal hematopoiesis is associated with cytopenia, suggesting an...
Abstract T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples resistant to killing by human-engineered cytotoxic CD4 + cells. Single-cell RNA-seq primary before after their interaction uncovered transcriptional programs correlate with sensitivity or resistance cell killing. Resistance-associated were enriched in patients poor survival, killing-resistant did not engage vitro. Killing-sensitive...
Cancer-related anemia is present in more than 60% of newly diagnosed cancer patients and associated with substantial morbidity high medical costs. Drugs that enhance erythropoiesis are urgently required to decrease transfusion rates improve quality life. Clinical studies have observed an unexpected improvement hemoglobin RBC transfusion-independence acute myeloid leukemia (AML) treated the isocitrate dehydrogenase 2 (IDH2) mutant-specific inhibitor enasidenib, leading improved life without a...
Abstract Small molecule tyrosine kinase inhibitors (TKI) have revolutionized cancer treatment and greatly improved patient survival. However, life-threatening cardiotoxicity of many TKIs has become a major concern. Ponatinib (ICLUSIG) was developed as an inhibitor the BCR-ABL oncogene is among most cardiotoxic TKIs. Consequently, use ponatinib restricted to tumors carrying T315I-mutated BCR-ABL, which occurs in chronic myeloid leukemia (CML) confers resistance first- second-generation such...
Abstract Recombination-activating genes (RAG1 and RAG2) are critical for lymphoid cell development function by initiating the variable (V), diversity (D), joining (J) (V(D)J)-recombination process to generate polyclonal lymphocytes with broad antigen specificity. The clinical manifestations of defective RAG1/2 range from immune dysregulation severe combined immunodeficiencies (SCIDs), causing life-threatening infections death early in life without hematopoietic transplantation (HCT). Despite...
Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, role of leukemogenesis is not fully understood, effective therapies for RUNX1-mutant remain elusive. Here, we used primary patient samples a RUNX1-KO model human hematopoietic cells to investigate how loss contributes leukemic progression identify targetable vulnerabilities. Surprisingly, found decreased proliferative capacity...
Highlights•Polyvinyl alcohol (PVA) stabilizes recombinant cytokines in liquid media.•PVA supports albumin-free growth of cytokine-dependent leukemia cells.•PVA can replace serum albumin for ex vivo expansion functional CAR T cells.AbstractSerum has long been an essential supplement hematopoietic and immune cell cultures. However, medium supplements represent a major source biological contamination cultures often cause loss cellular function. As exhibits significant batch-to-batch...
Hematopoietic multipotent progenitors (MPPs) regulate blood cell production to appropriately meet the biological demands of human body. Human MPPs remain ill-defined whereas mouse have been well characterized with distinct immunophenotypes and lineage potencies. Using multiomic single analyses complementary functional assays, we identified new oligopotent progenitor populations within Lin-CD34+CD38dim/lo adult bone marrow biomolecular properties. These were prospectively isolated based on...
Genetic mutations are being thoroughly mapped in human cancers, yet a fundamental question cancer biology is whether such functionally required for initiation, maintenance of established cancer, or both. Here, we study this the context acute myeloid leukemia (AML), where DNMT3AR882 missense often arise early, pre-leukemic clonal hematopoiesis, and corrupt DNA methylation landscape to initiate leukemia. We developed CRISPR-based methods directly correct leukemic cells obtained from patients....
Graft-versus-host disease (GVHD), mediated by donor-derived alloreactive T cells, is a major cause of nonrelapse mortality in allogeneic hematopoietic stem cell transplantation. Its therapy not well-defined. We established allele-specific anti-human leukocyte antigen (HLA) monoclonal antibodies (ASHmAbs) that specifically target HLA molecules, with steady death target-expressing cells. One such ASHmAb, against HLA-A*02:01 (A2-kASHmAb), was examined xenogeneic GVHD mouse model. To induce...
To develop a new therapeutic monoclonal Antibody (mAb) for Hodgkin lymphoma (HL), we immunized BALB/c mouse with live HL cell lines, alternating between two lines. After hybridization, screened the hybridoma clones by assessing direct cytotoxicity against line not used immunization. We developed this strategy establishing mAb to reduce risk of obtaining clonotypic specific single line. A newly established anti-human (4713) triggered cytoskeleton-dependent, but complement- and...
Despite the complexity of hematopoietic cell transplantation in humans, researchers commonly perform intravenous or intrafemoral (IF) injections mice. In murine models, this technique has been adapted to enhance seeding efficiency transplanted stem and progenitor cells (HSPCs). This paper describes a detailed step-by-step technical procedure IF injection following bone marrow (BM) aspiration mice that allows for serial characterization present BM. method enables valuable samples with low...
ABSTRACT Recombination-activating genes ( RAG1 and RAG2 ) are critical in lymphoid cell development function for initiating the V(D)J-recombination process to generate polyclonal lymphocytes with broad antigen-specificity. Clinical manifestations of defective RAG1/2 range from immune dysregulation severe combined immunodeficiencies (SCID), causing life-threatening infections death early life absence hematopoietic transplantation (HCT). Haploidentical HCT without myeloablative conditioning...
<div>Abstract<p>Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at time of acute myeloid leukemia (AML) diagnosis. pHSCs are origin and a potential reservoir for relapse. Using primary human samples gene editing to model <i>isocitrate dehydrogenase 1</i> (<i>IDH1</i>) mutant pHSCs, we show epigenetic, transcriptional, metabolic differences between healthy (HSC). We confirm that...