Updated on 2025/05/12

Information

 

写真a

 
KUNISAKI YUYA
 
Organization
Faculty of Medical Sciences Department of Basic Medicine Professor
School of Medicine Department of Medicine(Concurrent)
Graduate School of Medical Sciences Department of Medicine(Concurrent)
Graduate School of Medical Sciences Department of Health Care Administration and Management(Concurrent)
Title
Professor
Tel
0926425947
External link

Research Areas

  • Life Science / General internal medicine

Degree

  • MD,PhD

Research History

  • 九州厚生年金病院 亀田総合病院   

    九州厚生年金病院 亀田総合病院

  • マウントサイナイ医科大学 アルバートアインシュタイン医科大学   

Education

  • Kyushu University    

Research Interests・Research Keywords

  • Research theme: Hematopoietic stem cell niches

    Keyword: Stem cells

    Research period: 2014.4 - 2030.3

Papers

  • POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis Invited Reviewed International journal

    Nakashima K, Kunisaki Y, Hosokawa K, Gotoh K, Yao H, Yuta R, Semba Y, Nogami J, Kikushige Y, Stumpf PS, MacArthur BD, Kang D, Akashi K, Ohga S, Arai F.

    Commun Biol.   6 ( 1 )   996   2023.9   eISSN:2399-3642

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Communications Biology  

    Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.

    DOI: 10.1038/s42003-023-05374-0

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  • Regnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis Invited Reviewed International journal

    Kidoya, Hiroyasu; Muramatsu, Fumitaka; Shimamura, Teppei; Jia, Weizhen; Satoh, Takashi; Hayashi, Yumiko; Naito, Hisamichi; Kunisaki, Yuya; Arai, Fumio; Seki, Masahide; Suzuki, Yutaka; Osawa, Tsuyoshi; Akira, Shizuo; Takakura, Nobuyuki

    2019.3

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  • Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer. Reviewed International journal

    Nakano, Michitaka; Kikushige, Yoshikane; Miyawaki, Kohta; Kunisaki, Yuya; Mizuno, Shinichi; Takenaka, Katsuto; Tamura, Shingo; Okumura, Yuta; Ito, Mamoru; Ariyama, Hiroshi; Kusaba, Hitoshi; Nakamura, Masafumi; Maeda, Takahiro; Baba, Eishi; Akashi, Koichi

    2019.2

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    DOI: 10.1038/s41388-018-0480-0.

  • Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth Reviewed International journal

    Oshima, Tsuyoshi; Niwa, Yoshimi; Kuwata, Keiko; Srivastava, Ashutosh; Hyoda, Tomoko; Tsuchiya, Yoshiki; Kumagai, Megumi; Tsuyuguchi, Masato; Tamaru, Teruya; Sugiyama, Akiko; Ono, Natsuko; Zolboot, Norjin; Aikawa, Yoshiki; Oishi, Shunsuke; Nonami, Atsushi; Arai, Fumio; Hagihara, Shinya; Yamaguchi, Junichiro; Tama, Florence; Kunisaki, Yuya; Yagita, Kazuhiro; Ikeda, Masaaki; Kinoshita, Takayoshi; Kay, Steve A.; Itami, Kenichiro; Hirota, Tsuyoshi

    2019.1

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    DOI: 10.1126/sciadv.aau9060.

  • Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion

    國﨑 祐哉

    NATURE MEDICINE   20 ( 11 )   2014.11

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  • Arteriolar niches maintain haematopoietic stem cell quiescence. Reviewed International journal

    Yuya Kunisaki

    Nature   502 ( 7473 )   637 - 643   2013.10

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    DOI: 10.1007/s12185-014-1580-4

  • Adrenergic nerves govern circadian leukocyte recruitment to tissues. Reviewed International journal

    Yuya Kunisaki

    Immunity   37 ( 2 )   190 - 198   2012.8

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    DOI: 10.1016/j.immuni.2012.05.021.

  • DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis. Reviewed International journal

    Yuya Kunisaki

    J Cell Biol   174 ( 5 )   647 - 652   2006.8

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  • DOCK2 is required in T cell precursors for development of Valpha14 NK T cells. Reviewed International journal

    Yuya Kunisaki

    J Immunol   176 ( 8 )   4640 - 4645   2006.4

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  • Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor. Reviewed International journal

    Yuya Kunisaki

    blood   103 ( 9 )   3363 - 3364   2004.5

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  • Objective quantification of pre-CAR-T EEG abnormalities for ICANS prognosis: insights from GTE scoring.

    Nakagaki H, Yamauchi T, Mukaino T, Sakata A, Watanabe E, Watanabe M, Ishihara D, Imanaga H, Sasaki K, Sakoda T, Jinnouchi F, Miyawaki K, Shima T, Kikushige Y, Mori Y, Hotta T, Kunisaki Y, Shigeto H, Isobe N, Akashi K, Kato K

    Bone marrow transplantation   2025.4   ISSN:0268-3369

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    DOI: 10.1038/s41409-025-02616-z

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  • Monitoring circulating tumor DNA by recurrent hotspot mutations in bladder cancer.

    Tsukahara S, Shiota M, Matsumoto T, Takamatsu D, Nagakawa S, Noda N, Matsumoto S, Yagi M, Uchiumi T, Kunisaki Y, Kang D, Eto M

    BJC reports   3 ( 1 )   26   2025.4

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    DOI: 10.1038/s44276-025-00143-4

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  • Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of <i>PML::RARα</i>

    Minami, M; Sakoda, T; Kawano, G; Kochi, Y; Sasaki, K; Sugio, T; Jinnouchi, F; Miyawaki, K; Kunisaki, Y; Kato, K; Miyamoto, T; Akashi, K; Kikushige, Y

    LEUKEMIA   39 ( 4 )   844 - 853   2025.4   ISSN:0887-6924 eISSN:1476-5551

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    Language:English   Publisher:Leukemia  

    Leukemic stem cells (LSCs) of acute myeloid leukemia (AML) can be enriched in the CD34+CD38- fraction and reconstitute human AML in vivo. However, in acute promyelocytic leukemia (APL), which constitutes 10% of all AML cases and is driven by promyelocytic leukemia-retinoic acid receptor alpha (PML::RARα) fusion genes, the presence of LSCs has long been unidentified because of the difficulty in efficient reconstitution of human APL in vivo. Herein, we show that LSCs of the short-type isoform APL, a subtype of APL defined by different breakpoints of the PML gene, concentrate in the CD34+CD38− fraction and express T cell immunoglobulin mucin-3 (TIM-3). Short-type APL cells exhibited distinct gene expression signatures, including LSC-related genes, compared to the other types of APL. Moreover, CD34+CD38−TIM-3+ short-type APL cells efficiently reconstituted human APL in xenograft models with high penetration, whereas CD34− differentiated APL cells did not. Furthermore, CD34+CD38−TIM-3+ short-type APL cells reconstituted leukemia cells after serial transplantation. Thus, short-type APL was hierarchically organized by self-renewing APL-LSCs. The identification of LSCs in a subset of APL and establishment of an efficient patient-derived xenograft model may contribute to further understanding the APL leukemogenesis and devise individual treatments for the eradication of APL LSCs.

    DOI: 10.1038/s41375-025-02530-9

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  • Cerebrospinal fluid proteomics exerts predictive potential for immune effector cell-associated neurotoxicity syndrome (ICANS) in CAR-T cell therapy

    Nomiyama, T; Setoyama, D; Yamanaka, I; Shimo, M; Miyawaki, K; Yamauchi, T; Jinnouchi, F; Sakoda, T; Sasaki, K; Shima, T; Kikushige, Y; Mori, Y; Akashi, K; Kato, K; Kunisaki, Y

    LEUKEMIA   39 ( 4 )   983 - 987   2025.4   ISSN:0887-6924 eISSN:1476-5551

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    DOI: 10.1038/s41375-025-02541-6

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  • Indirect presentation of mismatched human leukocyte antigen-B associates with outcomes of cord blood transplantation

    Sugio, T; Miyawaki, K; Uchida, N; Niemann, M; Spierings, E; Mori, K; Ohno, Y; Eto, T; Mori, Y; Yoshimoto, G; Kikushige, Y; Kunisaki, Y; Mizuno, S; Nagafuji, K; Iwasaki, H; Kamimura, T; Ogawa, R; Miyamoto, T; Taniguchi, S; Akashi, K; Kato, K

    BRITISH JOURNAL OF HAEMATOLOGY   2025.3   ISSN:0007-1048 eISSN:1365-2141

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    Cord blood transplantation (CBT) is a valuable donor source for patients without human leukocyte antigen (HLA)-matched donors. While CBT has a lower risk of graft-versus-host disease and requires less stringent histocompatibility, it is associated with a higher transplantation-related mortality (TRM) compared to other donor sources. We hypothesized that assessing the immunogenicity of mismatched HLA could reveal non-permissive mismatches contributing to increased TRM. We retrospectively analysed 1498 single-unit CBT cases from 2000 to 2018 across eight Japanese institutions, evaluating the immunogenicity of mismatched HLA using the PIRCHE algorithm to examine binding affinities of HLA-derived epitopes to donor or recipient HLA. Results indicated that Class I epitopes from mismatched recipient HLA-B were significantly associated with poor outcomes due to higher TRM and lower neutrophil engraftment, particularly when presented on matched HLA class I. Notably, epitopes from HLA-B exon 1 showed stronger prognostic significance, with HLA-B alleles carrying M-type leader peptides exhibiting higher affinity for these epitopes. Patients with a matched M-type HLA-B and Class I epitopes derived from mismatched HLA-B exon 1 had worse outcomes. These findings suggest that immunogenicity-informed donor selection could improve CBT outcomes.

    DOI: 10.1111/bjh.20035

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  • Homeostatic signals, including IL-7 and self-MHC recognition, induce the development of peripheral helper T cells, which are enriched in the joints of rheumatoid arthritis

    Tsurui, R; Yamada, H; Natori, T; Yoshimura, M; Akasaki, Y; Kawahara, S; Niiro, H; Kunisaki, Y; Nakashima, Y

    JOURNAL OF TRANSLATIONAL AUTOIMMUNITY   9   100258   2024.12   ISSN:2589-9090

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    Language:English   Publisher:Journal of Translational Autoimmunity  

    Objective: Dysregulated T cell homeostasis has long been implicated in the pathogenesis of rheumatoid arthritis (RA), in the joint of which peripheral helper T (Tph) cells accumulate and form ectopic lymphoid organs. We examined whether homeostatic signals are involved in the development of Tph cells. Methods: Human peripheral blood mononuclear cells were cultured with IL-7, the critical cytokine for T cell homeostasis. Development of Tph-like cells was assessed by flow cytometry, gene expression, and functional analysis. Chemotaxis of the Tph-like cells to RA synovial fluid (RASF) and the effect of RASF on the development of Tph-like cells was examined. Results: PD-1highCXCR5- Tph-like cells developed from human peripheral blood CD4 T cells after proliferation in response to IL-7. Signals from self-MHC recognition and CD28 co-stimulation were also involved. The IL-7-induced Tph-like (IL-7-Tph) cells produced CXCL13 and IL-21 and helped B cells produce IgG. Comprehensive gene expression analysis further supported the similarity with Tph cells in RA joint. IL-7-Tph cells exhibited chemotaxis toward synovial fluid from RA patients (RASF), and RASF promoted the development of IL-7-Tph cells, which were also induced from CD4 T cells residing in non-inflamed joints. Conclusions: Our results demonstrate an antigen-nonspecific developmental pathway of Tph cells triggered by homeostatic signals and promoted by the local environment of RA, which accounts for the accumulation of Tph cells in inflamed joints.

    DOI: 10.1016/j.jtauto.2024.100258

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  • Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma

    Miki, K; Yagi, M; Hatae, R; Otsuji, R; Miyazaki, T; Goto, K; Setoyama, D; Fujioka, Y; Sangatsuda, Y; Kuga, D; Higa, N; Takajo, T; Hajime, Y; Akahane, T; Tanimoto, A; Hanaya, R; Kunisaki, Y; Uchiumi, T; Yoshimoto, K

    CANCER & METABOLISM   12 ( 1 )   35   2024.11   ISSN:2049-3002 eISSN:2049-3002

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  • Long-range and real-time PCR identification of a large <i>SERPINC1</i> deletion in a patient with antithrombin deficiency

    Matsumoto, S; Uchiumi, T; Ueyanagi, Y; Noda, N; Sakai, A; Hotta, T; Kato, K; Ohga, S; Kunisaki, Y; Kang, DC

    INTERNATIONAL JOURNAL OF HEMATOLOGY   120 ( 2 )   179 - 185   2024.8   ISSN:0925-5710 eISSN:1865-3774

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    Congenital antithrombin (AT) or serpin C1 deficiency, caused by a SERPINC1 abnormality, is a high-risk factor for venous thrombosis. SERPINC1 is prone to genetic rearrangement, because it contains numerous Alu elements. In this study, a Japanese patient who developed deep vein thrombosis during pregnancy and exhibited low AT activity underwent SERPINC1 gene analysis using routine methods: long-range polymerase chain reaction (PCR) and real-time PCR. Sequencing using long-range PCR products revealed no pathological variants in SERPINC1 exons or exon–intron junctions, and all the identified variants were homozygous, suggesting a deletion in one SERPINC1 allele. Copy number quantification for each SERPINC1 exon using real-time PCR revealed half the number of exon 1 and 2 copies compared with controls. Moreover, a deletion region was deduced by quantifying the 5′-upstream region copy number of SERPINC1 for each constant region. Direct long-range PCR sequencing with primers for the 5'-end of each presumed deletion region revealed a large Alu-mediated deletion (∼13 kb) involving SERPINC1 exons 1 and 2. Thus, a large deletion was identified in SERPINC1 using conventional PCR methods.

    DOI: 10.1007/s12185-024-03796-y

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  • Long-range and real-time PCR identification of a large SERPINC1 deletion in a patient with antithrombin deficiency(タイトル和訳中)

    Matsumoto Shinya, Uchiumi Takeshi, Ueyanagi Yasushi, Noda Nozomi, Sakai Atsuhiko, Hotta Taeko, Kato Kiyoko, Ohga Shouichi, Kunisaki Yuya, Kang Dongchon

    International Journal of Hematology   120 ( 2 )   179 - 185   2024.8   ISSN:0925-5710

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  • Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis

    Toshima, T; Yagi, M; Do, Y; Hirai, H; Kunisaki, Y; Kang, DC; Uchiumi, T

    LIFE SCIENCE ALLIANCE   7 ( 7 )   2024.7   eISSN:2575-1077

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    Neurodegenerative diseases and other age-related disorders are closely associated with mitochondrial dysfunction. We previously showed that mice with neuron-specific deficiency of mitochondrial translation exhibit leukoencephalopathy because of demyelination. Reduced cholesterol metabolism has been associated with demyelinating diseases of the brain such as Alzheimer’s disease. However, the molecular mechanisms involved and relevance to the pathogenesis remained unknown. In this study, we show that inhibition of mitochondrial translation significantly reduced expression of the cholesterol synthase genes and degraded their sterol-regulated transcription factor, sterol regulatory element-binding protein 2 (Srebp2). Further-more, the phosphorylation of Pyk2 and Gsk3β was increased in the white matter of p32cKO mice. We observed that Pyk2 inhibitors reduced the phosphorylation of Gsk3β and that GSK3β inhibitors suppressed degradation of the transcription factor Srebp2. The Pyk2–Gsk3β axis is involved in the ubiquitination of Srebp2 and reduced expression of cholesterol gene. These results suggest that inhibition of mitochondrial translation may be a causative mechanism of neurodegenerative diseases of aging. Improving the mitochondrial translation or effectiveness of Gsk3β inhibitors is a potential therapeutic strategy for leukoencephalopathy.

    DOI: 10.26508/lsa.202302423

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  • Glucose starvation causes ferroptosis-mediated lysosomal dysfunction

    Miki, K; Yagi, M; Kang, DC; Kunisaki, Y; Yoshimoto, K; Uchiumi, T

    ISCIENCE   27 ( 5 )   109735   2024.5   eISSN:2589-0042

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    Lysosomes, the hub of metabolic signaling, are associated with various diseases and participate in autophagy by supplying nutrients to cells under nutrient starvation. However, their function and regulation under glucose starvation remain unclear and are studied herein. Under glucose starvation, lysosomal protein expression decreased, leading to the accumulation of damaged lysosomes. Subsequently, cell death occurred via ferroptosis and iron accumulation due to DMT1 degradation. GPX4, a key factor in ferroptosis inhibition located on the outer membrane of lysosomes, accumulated in lysosomes, especially under glucose starvation, to protect cells from ferroptosis. ALDOA, GAPDH, NAMPT, and PGK1 are also located on the outer membrane of lysosomes and participate in lysosomal function. These enzymes did not function effectively under glucose starvation, leading to lysosomal dysfunction and ferroptosis. These findings may facilitate the treatment of lysosomal-related diseases.

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  • Cardiomyocyte-specific deletion of the mitochondrial transporter Abcb10 causes cardiac dysfunction via lysosomal-mediated ferroptosis

    Do, Y; Yagi, M; Hirai, H; Miki, K; Fukahori, Y; Setoyama, D; Yamamoto, M; Furukawa, T; Kunisaki, Y; Kang, DC; Uchiumi, T

    BIOSCIENCE REPORTS   44 ( 5 )   2024.5   ISSN:0144-8463 eISSN:1573-4935

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    Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here, we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.

    DOI: 10.1042/BSR20231992

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  • Prognostic impact of HLA supertype mismatch in single-unit cord blood transplantation Invited Reviewed International journal

    Sugio T, Uchida N, Miyawaki K, Ohno Y, Eto T, Mori Y, Yoshimoto G, Kikushige Y, Kunisaki Y, Mizuno S, Nagafuji K, Iwasaki H, Kamimura T, Ogawa R, Miyamoto T, Taniguchi S, Akashi K, Kato K.

    Bone Marrow Transplant   59 ( 4 )   466 - 472   2024.4   ISSN:0268-3369 eISSN:1476-5365

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Bone Marrow Transplantation  

    The “human leukocyte antigen (HLA) supertype” is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p = 0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR = 1.24, p = 0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.

    DOI: 10.1038/s41409-023-02183-1

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  • Collagen Lattice Model, Populated with Heterogeneous Cancer-Associated Fibroblasts, Facilitates Advanced Reconstruction of Pancreatic Cancer Microenvironment Invited Reviewed International journal

    Song X, Nihashi Y, Imai Y, Mori N, Kagaya N, Suenaga H, Shin-Ya K, Yamamoto M, Setoyama D, Kunisaki Y, Kida YS.

    Int J Mol Sci   25 ( 7 )   2024.3   ISSN:1661-6596 eISSN:1422-0067

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:International Journal of Molecular Sciences  

    Pancreatic ductal adenocarcinoma (PDAC) is a solid-tumor malignancy. To enhance the treatment landscape of PDAC, a 3D model optimized for rigorous drug screening is essential. Within the PDAC tumor microenvironment, a dense stroma comprising a large extracellular matrix and cancer-associated fibroblasts (CAFs) is well-known for its vital role in modulating tumor growth, cellular heterogeneity, bidirectional paracrine signaling, and chemoresistance. In this study, we employed a fibroblast-populated collagen lattice (FPCL) modeling approach that has the ability to replicate fibroblast contractility in the collagenous matrix to build dense stroma. This FPCL model allows CAF differentiation by facilitating multifaceted cell–cell interactions between cancer cells and CAFs, with the differentiation further influenced by mechanical forces and hypoxia carried within the 3D structure. Our FPCL models displayed hallmark features, including ductal gland structures and differentiated CAFs with spindle shapes. Through morphological explorations alongside in-depth transcriptomic and metabolomic profiling, we identified substantial molecular shifts from the nascent to mature model stages and potential metabolic biomarkers, such as proline. The initial pharmacological assays highlighted the effectiveness of our FPCL model in screening for improved therapeutic strategies. In conclusion, our PDAC modeling platform mirrors complex tumor microenvironmental dynamics and offers an unparalleled perspective for therapeutic exploration.

    DOI: 10.3390/ijms25073740

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  • Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug-induced thromboembolism Invited Reviewed International journal

    Hatakeyama K, Kikushige Y, Ishihara D, Yamamoto S, Kawano G, Tochigi T, Miyamoto T, Sakoda T, Christoforou A, Kunisaki Y, Fukata M, Kato K, Ito T, Handa H, Akashi K.

    Blood Adv   8 ( 3 )   785 - 796   2024.2   ISSN:2473-9529 eISSN:2473-9537

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Blood Advances  

    Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography–mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

    DOI: 10.1182/bloodadvances.2023010080

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  • Exploring the Role of Desmoplastic Physical Stroma in Pancreatic Cancer Progression Using a Three-Dimensional Collagen Matrix Model Invited Reviewed International journal

    Song X, Nihashi Y, Yamamoto M, Setoyama D, Kunisaki Y, Kida YS.

    Bioengineering (Basel)   10 ( 12 )   2023.12   ISSN:2306-5354 eISSN:2306-5354

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Bioengineering  

    Pancreatic ductal adenocarcinoma (PDAC) is a refractory tumor with a poor prognosis, and its complex microenvironment is characterized by a fibrous interstitial matrix surrounding PDAC cells. Type I collagen is a major component of this interstitial matrix. Abundant type I collagen promotes its deposition and cross-linking to form a rigid and dense physical barrier, which limits drug penetration and immune cell infiltration and provides drug resistance and metabolic adaptations. In this study, to identify the physical effect of the stroma, type I collagen was used as a 3D matrix to culture Capan-1 cells and generate a 3D PDAC model. Using transcriptome analysis, a link between type I collagen-induced physical effects and the promotion of Capan-1 cell proliferation and migration was determined. Moreover, metabolomic analysis revealed that the physical effect caused a shift in metabolism toward a glycolytic phenotype. In particular, the high expression of proline in the metabolites suggests the ability to maintain Capan-1 cell proliferation under hypoxic and nutrient-depleted conditions. In conclusion, we identified type I collagen-induced physical effects in promoting Capan-1 cells, which cause PDAC progression, providing support for the role of dense stroma in the PDAC microenvironment and identifying a fundamental method for modeling the complex PDAC microenvironment.

    DOI: 10.3390/bioengineering10121437

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  • GPAM mediated lysophosphatidic acid synthesis regulates mitochondrial dynamics in acute myeloid leukemia Invited Reviewed International journal

    Irifune H, Kochi Y, Miyamoto T, Sakoda T, Kato K, Kunisaki Y, Akashi K, Kikushige Y.

    Cancer Sci.   114 ( 8 )   3247 - 3258   2023.8   ISSN:1347-9032 eISSN:1349-7006

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Cancer Science  

    Metabolic alterations, especially in the mitochondria, play important roles in several kinds of cancers, including acute myeloid leukemia (AML). However, AML-specific molecular mechanisms that regulate mitochondrial dynamics remain elusive. Through the metabolite screening comparing CD34+ AML cells and healthy hematopoietic stem/progenitor cells, we identified enhanced lysophosphatidic acid (LPA) synthesis activity in AML. LPA is synthesized from glycerol-3-phosphate by glycerol-3-phosphate acyltransferases (GPATs), rate-limiting enzymes of the LPA synthesis pathway. Among the four isozymes of GPATs, glycerol-3-phosphate acyltransferases, mitochondrial (GPAM) was highly expressed in AML cells, and the inhibition of LPA synthesis by silencing GPAM or FSG67 (a GPAM-inhibitor) significantly impaired AML propagation through the induction of mitochondrial fission, resulting in the suppression of oxidative phosphorylation and the elevation of reactive oxygen species. Notably, inhibition of this metabolic synthesis pathway by FSG67 administration did not affect normal human hematopoiesis in vivo. Therefore, the GPAM-mediated LPA synthesis pathway from G3P represents a critical metabolic mechanism that specifically regulates mitochondrial dynamics in human AML, and GPAM is a promising potential therapeutic target.

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  • GPAMを介したリゾホスファチジン酸合成は急性骨髄性白血病のミトコンドリア動態を制御する(GPAM mediated lysophosphatidic acid synthesis regulates mitochondrial dynamics in acute myeloid leukemia)

    Irifune Hidetoshi, Kochi Yu, Miyamoto Toshihiro, Sakoda Teppei, Kato Koji, Kunisaki Yuya, Akashi Koichi, Kikushige Yoshikane

    Cancer Science   114 ( 8 )   3247 - 3258   2023.8   ISSN:1347-9032

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    急性骨髄性白血病(AML)に特異的なミトコンドリア機能の制御に関与する分子メカニズムを検討した。CD34陽性AML細胞と健常な造血幹/前駆細胞を比較した代謝物スクリーニングを通じて、AMLにおけるリゾホスファチジン酸(LPA)合成活性の亢進を同定した。LPAは、LPA合成経路の律速酵素であるグリセロール-3-リン酸アシルトランスフェラーゼ(GPAT)によってグリセロール-3-リン酸から合成される。GPATの4つのアイソザイムのうち、グリセロール-3-リン酸アシルトランスフェラーゼ、ミトコンドリア(GPAM)がAML細胞で高発現していた。GPAMサイレンシングまたはFSG67(GPAM阻害剤)でLPA合成を阻害すると、ミトコンドリア分裂が誘導され、その結果、酸化的リン酸化が抑制され、活性酸素種が増加することで、AMLの増殖が著しく阻害された。さらに、FSG67によるGPAM阻害は、in vivoでの正常な造血に影響を与えることなく、AMLに対して有効であることが示された。以上より、GPAMを介したグリセロール-3-リン酸からのLPA合成経路は、AMLにおけるミトコンドリア動態を特異的に制御する重要な代謝機構であり、GPAMは有望な治療標的であることが示唆された。

  • Human acute leukemia uses branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function

    Kikushige, Y; Miyamoto, T; Kochi, Y; Semba, Y; Ohishi, M; Irifune, H; Hatakeyama, K; Kunisaki, Y; Sugio, T; Sakoda, T; Miyawaki, K; Kato, K; Soga, T; Akashi, K

    BLOOD ADVANCES   7 ( 14 )   3592 - 3603   2023.7   ISSN:2473-9529 eISSN:2473-9537

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    Cancer-specific metabolic activities play a crucial role in the pathogenesis of human malignancies. To investigate human acute leukemia–specific metabolic properties, we comprehensively measured the cellular metabolites within the CD34+ fraction of normal hematopoietic stem progenitor cells (HSPCs), primary human acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) cells. Here, we show that human leukemia cells are addicted to the branched-chain amino acid (BCAA) metabolism to maintain their stemness, irrespective of myeloid or lymphoid types. Human primary acute leukemias had BCAA transporters for BCAA uptake, cellular BCAA, α-ketoglutarate (α-KG), and cytoplasmic BCAA transaminase-1 (BCAT1) at significantly higher levels than control HSPCs. Isotope-tracing experiments showed that in primary leukemia cells, BCAT1 actively catabolizes BCAA using α-KG into branched-chain α-ketoacids, whose metabolic processes provide leukemia cells with critical substrates for the trichloroacetic acid cycle and the synthesis of nonessential amino acids, both of which reproduce α-KG to maintain its cellular level. In xenogeneic transplantation experiments, deprivation of BCAA from daily diet strongly inhibited expansion, engraftment and self-renewal of human acute leukemia cells. Inhibition of BCAA catabolism in primary AML or ALL cells specifically inactivates the function of the polycomb repressive complex 2, an epigenetic regulator for stem cell signatures, by inhibiting the transcription of PRC components, such as zeste homolog 2 and embryonic ectoderm development. Accordingly, BCAA catabolism plays an important role in the maintenance of stemness in primary human AML and ALL, and molecules related to the BCAA metabolism pathway should be critical targets for acute leukemia treatment.

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  • TIM-3 signaling hijacks the canonical Wnt/β-catenin pathway to maintain cancer stemness in acute myeloid leukemia

    Sakoda, T; Kikushige, Y; Miyamoto, T; Irifune, H; Harada, T; Hatakeyama, K; Kunisaki, Y; Kato, K; Akashi, K

    BLOOD ADVANCES   7 ( 10 )   2053 - 2065   2023.5   ISSN:2473-9529 eISSN:2473-9537

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    The activation of β-catenin plays critical roles in normal stem cell function, and, when aberrantly activated, the maintenance and enhancement of cancer stemness in many solid cancers. Aberrant β-catenin activation is also observed in acute myeloid leukemia (AML), and crucially contributes to self-renewal and propagation of leukemic stem cells (LSCs) regardless of mutations in contrast with such solid tumors. In this study, we showed that the AML-specific autocrine loop comprised of T-cell immunoglobulin mucin-3 (TIM-3) and its ligand, galectin-9 (Gal-9), drives the canonical Wnt pathway to stimulate self-renewal and propagation of LSCs, independent of Wnt ligands. Gal-9 ligation activates the cytoplasmic Src homology 2 domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase highly expressed in LSCs but not in HSCs, and HCK phosphorylates p120-catenin to promote formation of the LDL receptor–related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis is principally active in immature LSCs compared with TIM-3–expressed differentiated AML blasts and exhausted T cells. These data suggest that human AML LSCs constitutively activates β-catenin via autocrine TIM-3/HCK/p120-catenin signaling, and that molecules related to this signaling axis should be critical targets for selective eradication of LSCs without impairing normal HSCs.

    DOI: 10.1182/bloodadvances.2022008405

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  • Generation of functional oocytes from male mice in vitro Invited Reviewed International journal

    Murakami, Kenta; Hamazaki, Nobuhiko; Hamada, Norio; Nagamatsu, Go; Okamoto, Ikuhiro; Ohta, Hiroshi; Nosaka, Yoshiaki; Ishikura, Yukiko; Kitajima, Tomoya S.; Semba, Yuichiro; Kunisaki, Yuya; Arai, Fumio; Akashi, Koichi; Saitou, Mitinori; Kato, Kiyoko; Hayashi, Katsuhiko

    NATURE   615 ( 7954 )   900 - +   2023.3   ISSN:0028-0836 eISSN:1476-4687

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    Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes1–5. Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down’s syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.

    DOI: 10.1038/s41586-023-05834-x

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  • Successful pseudo-autologous stem cell transplantation for donor-derived Burkitt lymphoma occurring 9 years after allogeneic transplantation

    Taniguchi, S; Utsumi, S; Kochi, Y; Taya, Y; Mori, Y; Semba, YI; Sugio, T; Miyawaki, K; Kikushige, Y; Kunisaki, Y; Yoshimoto, G; Numata, A; Kato, K; Uchida, N; Maeda, T; Miyamoto, T; Taniguchi, S; Akashi, K

    INTERNATIONAL JOURNAL OF HEMATOLOGY   117 ( 2 )   287 - 292   2023.2   ISSN:0925-5710 eISSN:1865-3774

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    Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34+ cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23 months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD.

    DOI: 10.1007/s12185-022-03458-x

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  • Prognostic value of pre-transplantation total metabolic tumor volume on <SUP>18</SUP>fluoro-2-deoxy-d-glucose positron emission tomography-computed tomography in relapsed and refractory aggressive lymphoma

    Sugio, T; Baba, S; Mori, Y; Yoshimoto, G; Kamesaki, K; Takashima, S; Urata, S; Shima, T; Miyawaki, K; Kikushige, Y; Kunisaki, Y; Numata, A; Takenaka, K; Iawasaki, H; Miyamoto, T; Ishigami, K; Akashi, K; Kato, K

    INTERNATIONAL JOURNAL OF HEMATOLOGY   116 ( 4 )   603 - 611   2022.10   ISSN:0925-5710 eISSN:1865-3774

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    Relapsed and refractory aggressive lymphoma have a poor prognosis. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is effective in chemosensitive patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is among the few options for non-chemosensitive patients. 18Fluoro-2-deoxy-d-glucose positron emission tomography–computed tomography (18FDG-PET/CT) is the standard tool for evaluating response to chemotherapy and residual tumor volume. However, accurate assessment of residual tumor volume is not currently being achieved in clinical practice, and its value in prognostic and therapeutic stratification remains unclear. To answer this question, we investigated the efficacy of quantitative indicators, including total metabolic tumor volume (TMTV), in predicting prognosis after auto-HSCT and allo-HSCT. We retrospectively analyzed 39 patients who received auto-HSCT and 28 who received allo-HSCT. In the auto-HSCT group, patients with a higher TMTV had a poor prognosis due to greater risk of relapse. In the allo-HSCT group, patients with a higher TMTV had a lower progression-free survival rate and a significantly higher relapse rate. Neither Deauville score nor other clinical parameters were associated with prognosis in either group. Therefore, pre-transplant TMTV on PET is effective for prognostic prediction and therapeutic decision-making for relapsed or refractory aggressive lymphoma.

    DOI: 10.1007/s12185-022-03394-w

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  • Risk factors for late cytomegalovirus infection after completing letermovir prophylaxis

    Mori, Y; Harada, T; Yoshimoto, G; Shima, T; Numata, A; Jinnouchi, F; Yamauchi, T; Kikushige, Y; Kunisaki, Y; Kato, K; Takenaka, K; Akashi, K; Miyamoto, T

    INTERNATIONAL JOURNAL OF HEMATOLOGY   116 ( 2 )   258 - 265   2022.8   ISSN:0925-5710 eISSN:1865-3774

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    Prophylactic use of letermovir (LMV) markedly reduces the incidence of early clinically significant cytomegalovirus (csCMV) infection within the first 100 days after allogeneic hematopoietic cell transplantation (allo-HCT), which improves transplant outcomes. However, some patients eventually develop late-csCMV infection (beyond day 100) after completing LMV prophylaxis. To assess the incidence of late-csCMV infection as well as its risk factors and impacts on transplant outcome, a total of 81 allo-HCT recipients who had not developed early csCMV infection during LMV prophylaxis were retrospectively analyzed. Among them, 23 (28.4%) patients developed late-csCMV infection (until day 180) at a median time of 131 days after transplantation and 30 days after LMV discontinuation, respectively. Late-csCMV infection was correlated with apparent delayed immune reconstitution: patients transplanted from HLA-mismatched donors (hazard ratio [HR] = 13.0, p = 0.011) or CMV-IgG-negative donors (HR = 2.39, p = 0.043) had a significantly higher risk. In this study, transplant outcomes did not differ between patients with and without late-csCMV infection. This suggests a need to clarify the efficacy of extended administration of LMV for preventing late-csCMV infection in a larger number of allo-HCT recipients, especially those with “high-risk” donors.

    DOI: 10.1007/s12185-022-03348-2

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  • MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis Invited Reviewed International journal

    Hayashi, Yasutaka; Kawabata, Kimihito C.; Tanaka, Yosuke; Uehara, Yasufumi; Mabuchi, Yo; Murakami, Koichi; Nishiyama, Akira; Kiryu, Shigeru; Yoshioka, Yusuke; Ota, Yasunori; Sugiyama, Tatsuki; Mikami, Keiko; Tamura, Moe; Fukushima, Tsuyoshi; Asada, Shuhei; Takeda, Reina; Kunisaki, Yuya; Fukuyama, Tomofusa; Yokoyama, Kazuaki; Uchida, Tomoyuki; Hagihara, Masao; Ohno, Nobuhiro; Usuki, Kensuke; Tojo, Arinobu; Katayama, Yoshio; Goyama, Susumu; Arai, Fumio; Tamura, Tomohiko; Nagasawa, Takashi; Ochiya, Takahiro; Inoue, Daichi; Kitamura, Toshio

    CELL REPORTS   39 ( 6 )   110805   2022.5   ISSN:2211-1247

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    Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and frequent progression to leukemia. It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually dominate the bone marrow space. Despite several studies implicating mesenchymal stromal or stem cells (MSCs), a principal component of the HSC niche, in the inhibition of normal hematopoiesis, the molecular mechanisms underlying this process remain unclear. Here, we demonstrate that both human and mouse MDS cells perturb bone metabolism by suppressing the osteolineage differentiation of MSCs, which impairs the ability of MSCs to support normal HSCs. Enforced MSC differentiation rescues the suppressed normal hematopoiesis in both in vivo and in vitro MDS models. Intriguingly, the suppression effect is reversible and mediated by extracellular vesicles (EVs) derived from MDS cells. These findings shed light on the novel MDS EV-MSC axis in ineffective hematopoiesis.

    DOI: 10.1016/j.celrep.2022.110805

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  • A germinal center-associated microenvironmental signature reflects malignant phenotype and outcome of DLBCL Invited Reviewed International journal

    Miyawaki, Kohta; Kato, Koji; Sugio, Takeshi; Sasaki, Kensuke; Miyoshi, Hiroaki; Semba, Yuichiro; Kikushige, Yoshikane; Mori, Yasuo; Kunisaki, Yuya; Iwasaki, Hiromi; Miyamoto, Toshihiro; Kuo, Frank C.; Aster, Jon C.; Ohshima, Koichi; Maeda, Takahiro; Akashi, Koichi

    BLOOD ADVANCES   6 ( 7 )   2388 - 2402   2022.4   ISSN:2473-9529 eISSN:2473-9537

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    Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy, with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin (COO), genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.

    DOI: 10.1182/bloodadvances.2021004618

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  • Optimization of lymphapheresis for manufacturing autologous CAR-T cells Reviewed International journal

    Yamanaka I, Yamauchi T, Henzan T, Sakoda T, Miyamoto K, Mishima H, Ono H, Koga Y, Nakashima Y, Kato K, Miyamoto T, Mizuno S, Ogawa Y, Ohga S, Akashi K, Maeda T, Kunisaki Y.

    Int J Hematol.   114 ( 4 )   449 - 458   2021.10

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    DOI: 10.1007/s12185-021-03191-x

  • A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL Reviewed International journal

    Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.

    Blood Adv.   2021.10

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    DOI: 10.1182/bloodadvances

  • Granulocyte collection by polymorphonuclear cell-targeting apheresis with medium-molecular-weight hydroxyethyl starch Reviewed International journal

    Henzan T, Yamauchi T, Yamanaka I, Sakoda T, Semba Y, Hayashi M, Kikushige Y, Mishima H, Ishimura M, Koga Y, Miyamoto T, Ohga S, Akashi K, Maeda T, Kunisaki Y.

    Int J Hematol.   2021.8

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    DOI: 10.1007/s12185-021-03207-6

  • Transfer learning efficiently maps bone marrow cell types from mouse to human using single-cell RNA sequencing Invited Reviewed International journal

    Stumpf, Patrick S.; Du, Xin; Imanishi, Haruka; Kunisaki, Yuya; Semba, Yuichiro; Noble, Timothy; Smith, Rosanna C. G.; Rose-Zerili, Matthew; West, Jonathan J.; Oreffo, Richard O. C.; Farrahi, Katayoun; Niranjan, Mahesan; Akashi, Koichi; Arai, Fumio; MacArthur, Ben D.

    COMMUNICATIONS BIOLOGY   3 ( 1 )   2020.12

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    DOI: 10.1038/s42003-020-01463-6

  • Mitochondrial Protein Synthesis Is Essential for Terminal Differentiation of CD45(-) TER119(-) Erythroid and Lymphoid Progenitors Invited Reviewed International journal

    Gotoh, Kazuhito; Kunisaki, Yuya; Mizuguchi, Soichi; Setoyama, Daiki; Hosokawa, Kentaro; Yao, Hisayuki; Nakashima, Yuya; Yagi, Mikako; Uchiumi, Takeshi; Semba, Yuichiro; Nogami, Jumpei; Akashi, Koichi; Arai, Fumio; Kang, Dongchon

    ISCIENCE   23 ( 11 )   2020.11

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    DOI: 10.1016/j.isci.2020.101654

  • Identification of unipotent megakaryocyte progenitors in human hematopoiesis. Reviewed International journal

    Miyawaki K, Iwasaki H, Jiromaru T, Kusumoto H, Yurino A, Sugio T, Uehara Y, Odawara J, Daitoku S, Kunisaki Y, Mori Y, Arinobu Y, Tsuzuki H, Kikushige Y, Iino T, Kato K, Takenaka K, Miyamoto T, Maeda T, Akashi K

    Blood   2017.6

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  • Differential cytokine contributions of perivascular haematopoietic stem cell niches Reviewed International journal

    Asada N, Kunisaki Y, Pierce H, Wang Z, Fernandez NF, Birbair A, Ma’ayan A, Frenette PS.

    Nat Cell Biol.   2017.3

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  • Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations Reviewed International journal

    Yurino A, Takenaka K, Yamauchi T, Nunomura T, Uehara Y, Jinnouchi F, Miyawaki K, Kikushige Y, Kato K, Miyamoto T, Iwasaki H, Kunisaki Y, Akashi K

    Stem Cell Reports   2016.9

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  • Identification of a portal vessel-associated fetal liver stem cell niche Reviewed International journal

    Kahn J, Mendelson A, Kunisaki Y, Kou Y, Arnal-Estape A, Pinho S, Ciero P, Nakahara F, Ma’ayan A, Merad M, Bergman A, Frenette PS

    Science   2016.1

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  • Neutrophil ageing is regulated by the microbiome Reviewed International journal

    Zhang D, Chen G, Manwani D, Mortha A, Xu C, Faith JJ, Burk RD, Kunisaki Y, Jang JE, Scheiermann C, Merad M, Frenette PS

    Nature   2015.9

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  • Acute Myelogenous Leukemia-Induced Sympathetic Neuropathy Promotes Malignancy in an Altered Hematopoietic Stem Cell Niche

    Yuya Kunisaki

    CELL STEM CELL   15 ( 3 )   2014.9

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    DOI: 10.1016/j.stem.2014.06.020

  • Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development Reviewed International journal

    Mizoguchi T, Pinho S, Ahmed J, Kunisaki Y, Hanoun M, Mendelson A, Ono N, Kronenberg HM, Frenette PS

    2014.5

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Presentations

  • 間葉系幹細胞による造血幹細胞制御機構 Invited

    國崎 祐哉

    第122回日本解剖学会総会・全国学術集会  2017.3 

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    Event date: 2017.3 - 2018.3

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:長崎   Country:Japan  

  • NG2+ arteriolar parasites form niches for dormant hematopoietic stem cells International conference

    Yuya Kunisaki

    The 12th Stem Cell Research Symposium  2014.5 

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    Event date: 2014.5

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Centennial Hall Kyushu University   Country:Japan  

    Cell cycle quiescence is a critical feature contributing to hematopoietic stem cell (HSC) maintenance. Whether quiescence and proliferation of HSCs are regulated by spatially distinct niches is unclear. Whole-mount confocal immunofluorescence assessment revealed an evenly distributed sinusoidal network and rare small calibre arterioles specifically ensheathed by NG2+ perivascular cells, which were found predominantly in close proximity to the bone. We further found that ~40 % of HSCs were located within 20µm distance from arterioles. To assess the significance of this association, we developed a computational simulation, in which HSCs were randomly positioned on images of whole-mount prepared sterna. The observed mean distance to arterioles was statistically different from that of randomly placed HSCs. This suggests that the physical association of HSC with arterioles is significant. Prolonged quiescence is referred to as dormancy and tracked as label-retaining cells. We evaluated the spatial association of dormant HSCs with arterioles by pulse-chase experiments with EdU and found that significantly more EdU+ HSCs compared to total HSCs were located within 20µm distance from arterioles. To test the functional relevance, we evaluated HSC-arteriole associations in mice treated with 5FU. We found that on day 3 the vast majority of HSCs was closely associated with arterioles. These data together indicate that arterioles provide a milieu promoting quiescence for both HSCs and a safe harbor to protect them against genotoxic insults. To examine the function of NG2+ cells, we intercrossed NG2-creERTM with an inducible diphtheria toxin receptor (iDTR) line. Depletion of NG2+ cells changed HSC localization away from arterioles, and switched them into a non-quiescent state. In addition, we found a ~60% reduction in the number of HSCs in the BM. Taken together, these results suggest that periarteriolar NG2+ cells form dormant niches for HSCs and the presence of spatially distinct vascular niches for quiescent and non-quiescent (proliferating) HSCs in the BM.

  • Circadian Expression of Endothelial Selectins, Regulated by the Sympathetic Nervous System, Controls Peripheral Leukocyte Homeostasis. International conference

    Yuya Kunisaki

    アメリカ血液学会  2008.12 

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    Venue:San francisco   Country:United States  

  • Circadian Adrenergic Regulation of Bone Marrow Endothelial Adhesion Molecule Expression Impacts Progenitor Recruitment and Engraftment Efficiency. International conference

    Yuya Kunisaki

    アメリカ血液学会  2010.12 

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    Venue:Orlando   Country:United States  

  • Bone Marrow Arteriolar Niches Maintain Hematopoietic Stem Cell Quiescence. International conference

    Yuya Kunisaki

    アメリカ血液学会  2012.12 

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    Country:United States  

  • 骨髄微小環境のイメージング Invited

    國崎 祐哉

    第29回日本フローサイトメトリー学会学術集会  2019.5 

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    Event date: 2019.5

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:東京   Country:Japan  

  • 骨髄微小環境のイメージング Invited

    國崎 祐哉

    第31回日本整形外科学会基礎学術集会  2016.10 

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    Event date: 2016.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  • 間葉系幹細胞による造血幹細胞制御機構 Invited

    國崎 祐哉

    第60回日本リウマチ学会総会・学術集会  2016.4 

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    Event date: 2016.4

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:横浜   Country:Japan  

  • 造血幹細胞ニッチ

    國崎 祐哉

    血液学会学術集会  2015.10 

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    Event date: 2015.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  • Imaging of the hematopoietic stem cells and niches Invited International conference

    Yuya Kunisaki

    The International Society for EXPERIMENTAL HEMATOLOGY 44th Annual meeting  2015.9 

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    Event date: 2015.9

    Language:English   Presentation type:Symposium, workshop panel (public)  

    Venue:Kyoto   Country:Japan  

  • 骨髄微小環境による造血幹細胞制御機構 Invited

    國崎 祐哉

    第39回阿蘇シンポジウム  2015.7 

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    Event date: 2015.7 - 2015.8

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:熊本   Country:Japan  

  • 血管性ニッチによる造血幹細胞制御機構 Invited

    國崎 祐哉

    第33回日本骨代謝学会学術総会  2015.7 

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    Event date: 2015.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  • NG2+ arteriolar pericytes form niches for dormant hematopoietic stem cells Invited International conference

    Yuya Kunisaki

    US-Japan Meeting on Malignant Hematopoisis and Stem Cells  2015.3 

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    Event date: 2015.3

    Language:English   Presentation type:Oral presentation (general)  

    Country:United States  

  • Arteriolar niches for hematopoietic stem cells Invited International conference

    Yuya Kunisaki

    第24回Hot Spring Harbor Symposium  2014.11 

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    Event date: 2014.11

    Language:English   Presentation type:Oral presentation (general)  

    Venue:福岡   Country:Japan  

  • The distinct vascular niches determine hematopoietic stem cell fate Invited International conference

    Yuya Kunisaki

    第76回日本 血液学会学術集会  2014.10 

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    Event date: 2014.10 - 2014.11

    Language:English   Presentation type:Oral presentation (general)  

    Venue:大阪   Country:Japan  

  • 血管性ニッチによる造血幹細胞制御機構 Invited

    國崎 祐哉

    第87回日本生化学会大会  2014.10 

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    Event date: 2014.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:京都   Country:Japan  

  • 造血幹細胞ニッチと造血器腫瘍 Invited International conference

    國崎 祐哉

    第73回日本癌学会学術総会  2014.9 

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    Event date: 2014.9

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜   Country:Japan  

  • TET2クローン性造血はリンパ腫患者におけるアントラサイクリン誘発性心毒性の強力なリスク因子である(TET2 Clonal Hematopoiesis Represents a Strong Risk Factor for Anthracycline-Induced Cardiotoxicity in Lymphoma Patients)

    Hatakeyama Kiwamu, Kikushige Yoshikane, Semba Yuichirou, Moriyama Shohei, Harada Takuya, Wang Yuqing, Katou Kouji, Maeda Takahiro, Kunisaki Yuya, Fukata Mitsuhiro, Miyamoto Toshihiro, Hieda Michinari, Akashi Koichi

    日本循環器学会学術集会抄録集  2022.3  (一社)日本循環器学会

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    Language:English  

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MISC

  • Salazosulfapyridine induced hypersensitivity syndrome associated with reactivation of humanherpes virus 6.

    Yuya Kunisaki

    Internal Medicine   2003.2

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  • Pericytes in Bone Marrow.

    Yuya Kunisaki

    Adv Exp Med Biol.   2019.4

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    Language:English   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

    DOI: 10.1007/978-3-030-11093-2_6.

  • がん幹細胞とニッチ

    國﨑 祐哉

    日本臨床   2015.5

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

    The fate of stem cells is tightly controlled by specialized microenvironments (niches). Cell cycle quiescence is a key behavior of stem cells, which protects them from being exhausted by exogenous insults. Since the discovery of cancer stem cells, which are quiescent and thus resistant to anti-cancer therapy, there has been considerable interest regarding whether or not there are distinct niches for quiescent and expanding cancer cells, respectively. In our recent study using whole-mount immunofluorescence imaging techniques, we found that arteriolar niches promote hematopoietic stem cell (HSC) dormancy and that the NG2+ peri-arteriolar niche cells themselves are quiescent, suggesting that bone marrow arterioles comprise a specialized microenvironment that promotes quiescence of both HSCs and niche cells. In this review, we will argue about the advance of our knowledge on normal stem cell niches and the roles of microenvironments in cancer.

  • 血管性ニッチによる造血幹細胞制御

    國﨑 祐哉

    実験医学   2015.3

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    造血幹細胞の多くは、定常状態において、細胞周期静止期にあるが、需要に応じて自己増殖または、すべての血球系統に分化する機能を持つ造血器特異的幹細胞である。このような造血幹細胞の運命決定は、「造血幹細胞ニッチ」と呼ばれる機能的に特殊な骨髄微小環境によって厳格な制御を受けていると考えられている。しかしながら、静止状態、分化増殖といった造血幹細胞の異なる機能が、同じもしくは異なるニッチにより制御を受けているかは、不明であった。これまでの多くの研究により、様々な非血液細胞がニッチを構成していることが明らかとなっているが、骨髄内における静止状態の造血幹細胞の局在は、議論の的であった。我々は、レーザースピニングディスク共焦点顕微鏡を用いた骨髄ホールマウントイメージング技術を開発した。この技術は、骨髄における造血幹細胞の局在及び、ストローマ細胞との位置的な相関を正確に評価し、更に、このその有意性を、コンピューターシミュレーションを用いて評価することを可能とした。我々は、この新しい解析法により、静止状態にある造血幹細胞は、骨髄中の骨内膜下に多く存在する細動脈周囲に存在していること(細動脈性ニッチ)を明らかにした。その細動脈周囲に存在する血管周囲細胞を欠失させることにより、造血幹細胞は細動脈ニッチから骨髄洞ニッチへと局在が変化し、そこで細胞増殖が誘導され、その結果減少した。この新しいイメージング技術を用いて得られた知見とこれまでの報告より、造血幹細胞の静止状態と細胞増殖は解剖学的に異なる血管性ニッチにより制御を受けていることが明らかとなった。

  • 細動脈性ニッチが導く造血幹細胞ニッチモデル

    國﨑 祐哉

    血液フロンティア   2015.3

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    造血幹細胞の機能は,その微小環境(ニッチ)からの特異的なシグナルによって,厳格な制御を受けている。「骨芽細胞性ニッチ」と「血管性ニッチ」という概念が提唱されているが,その骨髄内局在は明確に示されておらず,また,この異なる2つのニッチが,どのように造血幹細胞の機能を制御しているかは明らかとなっていない。筆者らは,骨髄3次元イメージング技術を確立し,造血幹細胞の分布をより詳細に解析することにより,「骨髄細動脈ニッチ」を見出した。この「細動脈ニッチ」の存在により導かれる新たな造血幹細胞ニッチモデルについて議論する。

  • Influences of vascular niches on hematopoietic stem cell fate.

    Yuya Kunisaki

    Int J Hematol   2014.6

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  • The secrets of the bone marrow niche: Enigmatic niche brings challenge for HSC expansion.

    Yuya Kunisaki

    Nat Med   2012.6

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  • Marked improvement of cardiac function early after non-myeloablative BMT in a heavily transfused patient with severe aplastic anemia and heart failure.

    Yuya Kunisaki

    Bone Marrow Transplant   2007.9

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  • Detection of two cell populations corresponding to distinct maturation stages in API-2/MLT-positive mucosa-associated lymphoid tissue lymphoma cells proliferating in pleural effusion.

    Yuya Kunisaki

    Int J Hematol   2003.11

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Professional Memberships

  • 日本臨床検査医学会

Other

  • 日本学術振興会 海外特別研究員

    2008.4

  • 日本学術振興会特別研究員

    2006.4

Research Projects

  • 腫瘍細胞と骨髄微小環境の相互作用を標的とする新規造血器腫瘍制御法の開発

    Grant number:21H02950  2021 - 2023

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 骨髄アンジオクラインファクターを標的とした白血病治療法の検証

    2020 - 2021

    Grants-in-Aid for Scientific Research  AMED

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    Authorship:Coinvestigator(s)  Grant type:Competitive funding other than Grants-in-Aid for Scientific Research

  • 間葉系ニッチのシングルセルプロファイリングによる造血器腫瘍発症及び進展機構の解明

    Grant number:18H02841  2018 - 2020

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 白血病細胞-骨髄腫瘍血管を巡る負のスパイラルを断ち切る治療標的の同定

    Grant number:18076874  2018 - 2019

    Grants-in-Aid for Scientific Research  がん創薬シーズやバイオマーカー候補の探索に資する新規アプローチを含む標的探索研究

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    Authorship:Coinvestigator(s)  Grant type:Competitive funding other than Grants-in-Aid for Scientific Research

  • 幹細胞ニッチの機能破綻による発癌機構の解明

    Grant number:15H04859  2015 - 2017

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 幹細胞ニッチの機能破綻による発癌機構の解明

    2015 - 2017

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 生体イメージングを用いた神経による造血幹細胞ニッチ制御機構の解明

    2015 - 2016

    Grants-in-Aid for Scientific Research  Grant-in-Aid for challenging Exploratory Research

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 生体イメージングを用いた神経による造血幹細胞ニッチ制御機構の解明

    Grant number:15K15364  2015 - 2016

    Grants-in-Aid for Scientific Research  Grant-in-Aid for challenging Exploratory Research

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 造血幹細胞ニッチのイメージング

    2014.4 - 2021.3

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    Authorship:Principal investigator 

    The aim of this project is to dissect the hematopoietic stem cell niches and to identify the hierarchy of mesenchymal cells, which regulate hematopoietic stem cell fate, by using bone marrow 3 dimensional imaging techniques.

  • 3次元イメージングによる骨髄造血幹細胞ニッチの同定

    Grant number:26893185  2014

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Research Activity start-up

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    Authorship:Principal investigator  Grant type:Scientific research funding

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Educational Activities

  • 医学科 臨床検査医学講義世話人、大学院教育、学位審査

Class subject

  • 血液学

    2020.10 - 2021.3   Second semester

  • 生理学

    2020.10 - 2021.3   Second semester

  • 臨床医学

    2020.10 - 2021.3   Second semester

Media Coverage

  • CAR-Tのバイオマーカー発見 Newspaper, magazine

    科学新聞  2025.3

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    Author:Myself 

Travel Abroad

  • 2010.7 - 2014.3

    Staying countory name 1:United States   Staying institution name 1:アルバートアインシュタイン医科大学

  • 2007.5 - 2014.3

    Staying countory name 1:United States   Staying institution name 1:マウントサイナイ医科大学

    Staying countory name 2:United States   Staying institution name 2:アルバートアインシュタイン医科大学

Specialized clinical area

  • Biology / Medicine, Dentistry and Pharmacy / Internal Medicine / Hematology

Clinician qualification

  • Specialist

    The Japanese Society of Internal Medicine(JSIM)

Year of medical license acquisition

  • 2000

Notable Clinical Activities

  • 骨髄バンク調整医師