All Publications

  • Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells. Developmental cell Fowler, J. L., Zheng, S. L., Nguyen, A., Chen, A., Xiong, X., Chai, T., Chen, J. Y., Karigane, D., Banuelos, A. M., Niizuma, K., Kayamori, K., Nishimura, T., Cromer, M. K., Gonzalez-Perez, D., Mason, C., Liu, D. D., Yilmaz, L., Miquerol, L., Porteus, M. H., Luca, V. C., Majeti, R., Nakauchi, H., Red-Horse, K., Weissman, I. L., Ang, L. T., Loh, K. M. 2024


    The developmental origin of blood-forming hematopoietic stem cells (HSCs) is a longstanding question. Here, our non-invasive genetic lineage tracing in mouse embryos pinpoints that artery endothelial cells generate HSCs. Arteries are transiently competent to generate HSCs for 2.5 days (∼E8.5-E11) but subsequently cease, delimiting a narrow time frame for HSC formation in vivo. Guided by the arterial origins of blood, we efficiently and rapidly differentiate human pluripotent stem cells (hPSCs) into posterior primitive streak, lateral mesoderm, artery endothelium, hemogenic endothelium, and >90% pure hematopoietic progenitors within 10 days. hPSC-derived hematopoietic progenitors generate T, B, NK, erythroid, and myeloid cells in vitro and, critically, express hallmark HSC transcription factors HLF and HOXA5-HOXA10, which were previously challenging to upregulate. We differentiated hPSCs into highly enriched HLF+ HOXA+ hematopoietic progenitors with near-stoichiometric efficiency by blocking formation of unwanted lineages at each differentiation step. hPSC-derived HLF+ HOXA+ hematopoietic progenitors could avail both basic research and cellular therapies.

    View details for DOI 10.1016/j.devcel.2024.03.003

    View details for PubMedID 38569552

  • Transposable Elements Are Differentially Expressed in MDS Stem Cells in a DiseaseStage-Specific Manner Kurosawa, S., Oshima, M., Nakajima-Takagi, Y., Takayama, N., Shinoda, D., Kaito, S., Kamiya, T., Yamada, Y., Andoh, S., Kayamori, K., Sakaida, E., Sato, E., Yusa, N., Yokoyama, K., Nannya, Y., Tojo, A., Imoto, S., Rahmutulla, B., Kaneda, A., Yamaguchi, K., Furukawa, Y., Doki, N., Nishikawa, K., Ding, Y., Myojo, T., Harada, Y., Harada, H., Iwama, A. AMER SOC HEMATOLOGY. 2023
  • Preemptive Intervention in Airflow Obstruction Status Prevents the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Stem Cell Transplantation: Multicenter, Prospective Phase II Study (Chiba AFO-01) Tsukamoto, S., Kimura, K., Nakao, S., Takeda, Y., Ohwada, C., Shimizu, R., Nagao, Y., Shono, K., Onoda, M., Yokota, A., Arai, H., Utsu, Y., Masuda, S., Aotsuka, N., Shiko, Y., Ozawa, Y., Ishii, A., Matsui, S., Takaishi, K., Hino, Y., Kayamori, K., Oshima-Hasegawa, N., Mitsukawa, S., Muto, T., Mimura, N., Nakaseko, C., Sakaida, E. 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
  • 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
  • Genome-wide CRISPR screening uncovers potential targets and mechanisms of vincristine resistance in DLBCL. British journal of haematology He, M. Y., Kayamori, K. 2023


    In this issue, Rovsing et al. employ unbiased genome-wide CRISPR screening and functional cellular assays to investigate the cellular response to vincristine, an important component of the front-line DLBCL treatment R-CHOP. Their findings reveal intriguing targets and mechanisms that hold promise for enhancing DLBCL treatment and provide a foundation for the development of future drug regimens. This research prompts further exploration of the translational potential to advance more effective and individualized approaches in the clinical management of DLBCL. Commentary on: Rovsing et al. Resistance to vincristine in DLBCL by disruption of p53-induced cell cycle arrest and apoptosis mediated by KIF18B and USP28. Br J Haematol 2023 (Online ahead of print). doi:10.1111/bjh.18872.

    View details for DOI 10.1111/bjh.18900

    View details for PubMedID 37259613

  • Impact of standard-dose dipeptidyl peptidase-4 inhibitors on the incidence of graft-versus-host disease after allogeneic hematopoietic cell transplantation BONE MARROW TRANSPLANTATION Kimura, S., Shimizu, H., Miyazaki, T., Sakurai, M., Tanoue, S., Kayamori, K., Ohwada, C., Yoshimura, K., Nakasone, H., Ohashi, T., Shono, K., Tachibana, T., Hatano, K., Okada, K., Kimura, Y., Seo, S., Doki, N., Tanaka, M., Hatta, Y., Takahashi, S., Kanda, Y., Kanto Study Grp Cell Therapy 2022

    View details for DOI 10.1038/s41409-022-01901-5

    View details for Web of Science ID 000903983000001

    View details for PubMedID 36572728

  • Unraveling unique features of plasma cell clones in POEMS syndrome by single-cell analysis. JCI insight Isshiki, Y., Oshima, M., Mimura, N., Kayamori, K., Miyamoto-Nagai, Y., Seki, M., Nakajima-Takagi, Y., Kanamori, T., Iwamoto, E., Muto, T., Tsukamoto, S., Takeda, Y., Ohwada, C., Misawa, S., Ikeda, J., Sanada, M., Kuwabara, S., Suzuki, Y., Sakaida, E., Nakaseko, C., Iwama, A. 2022


    POEMS syndrome is a rare monoclonal plasma cell disorder with unique symptoms distinct from other plasma cell neoplasms, including high serum VEGF levels. Since the prospective isolation of POEMS clones has not yet been successful, their real nature remains unclear. We herein performed the single-cell RNA sequencing of bone marrow plasma cells from patients with POEMS syndrome and identified POEMS clones that had immunoglobulin lambda light chain (IGL) sequences (IGLV1-36, 40, 44, and 47) with amino acid changes specific to POEMS syndrome. The proportions of POEMS clones in plasma cells were markedly smaller (median: 12.9%) than in multiple myeloma (MM) (96-100%) and monoclonal gammopathy of undetermined significance (MGUS) patients (57-81%). Single-cell transcriptomes revealed that POEMS clones were CD19-negative, CD138-positive, and MHC class II-low, which allowed for their prospective isolation. POEMS clones expressed significantly lower levels of c-MYC and CCND1 than MM, accounting for their small size. VEGF mRNA was not up-regulated in POEMS clones, directly indicating that VEGF is not produced by POEMS clones. These results reveal unique features of POEMS clones and enhance our understanding of the pathogenesis of POEMS syndrome.

    View details for DOI 10.1172/jci.insight.151482

    View details for PubMedID 36129760

  • DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes BLOOD ADVANCES Kayamori, K., Nagai, Y., Zhong, C., Kaito, S., Shinoda, D., Koide, S., Kuribayashi, W., Oshima, M., Nakajima-Takagi, Y., Yamashita, M., Mimura, N., Becker, H., Izawa, K., Yamazaki, S., Iwano, S., Miyawaki, A., Ito, R., Tohyama, K., Lennox, W., Sheedy, J., Weetall, M., Sakaida, E., Yokote, K., Iwama, A. 2021; 5 (2): 438-450


    Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We investigated the efficacy of PTC299, a novel DHODH inhibitor, for myelodysplastic syndrome (MDS). PTC299 inhibited the proliferation of MDS cell lines, and this was rescued by exogenous uridine, which bypasses de novo pyrimidine synthesis. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents, such as decitabine, to inhibit the growth of MDS cells. This synergistic effect was confirmed in primary MDS samples. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Mechanistically, a treatment with PTC299 induced intra-S-phase arrest followed by apoptotic cell death. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. RNA-seq data revealed the marked downregulation of MYC target gene sets with PTC299 exposure. Transfection of MDS cell lines with MYC largely attenuated the growth inhibitory effects of PTC299, suggesting MYC as one of the major targets of PTC299. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS.

    View details for DOI 10.1182/bloodadvances.2020001461

    View details for Web of Science ID 000613791800011

    View details for PubMedID 33496740

    View details for PubMedCentralID PMC7839369

  • Efficacy of the novel tubulin polymerization inhibitor PTC-028 for myelodysplastic syndrome CANCER SCIENCE Zhong, C., Kayamori, K., Koide, S., Shinoda, D., Oshima, M., Nakajima-Takagi, Y., Nagai, Y., Mimura, N., Sakaida, E., Yamazaki, S., Iwano, S., Miyawaki, A., Ito, R., Tohyama, K., Yamaguchi, K., Furukawa, Y., Lennox, W., Sheedy, J., Weetall, M., Iwama, A. 2020; 111 (12): 4336-4347


    Monomer tubulin polymerize into microtubules, which are highly dynamic and play a critical role in mitosis. Therefore, microtubule dynamics are an important target for anticancer drugs. The inhibition of tubulin polymerization or depolymerization was previously targeted and exhibited efficacy against solid tumors. The novel small molecule PTC596 directly binds tubulin, inhibits microtubule polymerization, downregulates MCL-1, and induces p53-independent apoptosis in acute myeloid leukemia cells. We herein investigated the efficacy of PTC-028, a structural analog of PTC596, for myelodysplastic syndrome (MDS). PTC-028 suppressed growth and induced apoptosis in MDS cell lines. The efficacy of PTC028 in primary MDS samples was confirmed using cell proliferation assays. PTC-028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit growth and induce apoptosis in MDS cells. Mechanistically, a treatment with PTC-028 induced G2/M arrest followed by apoptotic cell death. We also assessed the efficacy of PTC-028 in a xenograft mouse model of MDS using the MDS cell line, MDS-L, and the AkaBLI bioluminescence imaging system, which is composed of AkaLumine-HCl and Akaluc. PTC-028 prolonged the survival of mice in xenograft models. The present results suggest a chemotherapeutic strategy for MDS through the disruption of microtubule dynamics in combination with DNA hypomethylating agents.

    View details for DOI 10.1111/cas.14684

    View details for Web of Science ID 000583289000001

    View details for PubMedID 33037737

    View details for PubMedCentralID PMC7734154

  • Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma HEMATOLOGY Kayamori, K., Shono, K., Onoda, M., Yokota, A. 2019; 24 (1): 52-59