村上 紘一 (ムラカミ コウイチ)

Murakami, Koichi

写真a

所属(所属キャンパス)

医学部 内科学教室(血液) (信濃町)

職名

助教(有期)

 

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  • A RUNX–CBFβ-driven enhancer directs the Irf8 dose-dependent lineage choice between DCs and monocytes

    Murakami K., Sasaki H., Nishiyama A., Kurotaki D., Kawase W., Ban T., Nakabayashi J., Kanzaki S., Sekita Y., Nakajima H., Ozato K., Kimura T., Tamura T.

    Nature Immunology (Nature Immunology)  22 ( 3 ) 301 - 311 2021年03月

    ISSN  15292908

     概要を見る

    The transcription factor IRF8 is essential for the development of monocytes and dendritic cells (DCs), whereas it inhibits neutrophilic differentiation. It is unclear how Irf8 expression is regulated and how this single transcription factor supports the generation of both monocytes and DCs. Here, we identified a RUNX–CBFβ-driven enhancer 56 kb downstream of the Irf8 transcription start site. Deletion of this enhancer in vivo significantly decreased Irf8 expression throughout the myeloid lineage from the progenitor stages, thus resulting in loss of common DC progenitors and overproduction of Ly6C+ monocytes. We demonstrated that high, low or null expression of IRF8 in hematopoietic progenitor cells promotes differentiation toward type 1 conventional DCs, Ly6C+ monocytes or neutrophils, respectively, via epigenetic regulation of distinct sets of enhancers in cooperation with other transcription factors. Our results illustrate the mechanism through which IRF8 controls the lineage choice in a dose-dependent manner within the myeloid cell system.

  • OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy

    Murakami K., Kurotaki D., Kawase W., Soma S., Fukuchi Y., Kunimoto H., Yoshimi R., Koide S., Oshima M., Hishiki T., Hayakawa N., Matsuura T., Oda M., Yanagisawa K., Kobayashi H., Haraguchi M., Atobe Y., Funakoshi K., Iwama A., Takubo K., Okamoto S., Tamura T., Nakajima H.

    Cell Reports (Cell Reports)  34 ( 1 )  2021年01月

     概要を見る

    O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.

  • O-GlcNAcylation: Implications in normal and malignant hematopoiesis

    Nakajima H., Murakami K.

    Experimental Hematology (Experimental Hematology)  2021年

    ISSN  0301472X

     概要を見る

    Posttranslational protein modification through addition of the O‐linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed O-GlcNAcylation, is a highly dynamic process conserved throughout eukaryotes. O-GlcNAcylation is reversibly catalyzed by a single pair of enzymes, O-GlcNAc transferase and O-GlcNAcase, and it acts as a fundamental regulator for a wide variety of biological processes including gene expression, cell cycle regulation, metabolism, stress response, cellular signaling, epigenetics, and proteostasis. O-GlcNAcylation is regulated by various intracellular or extracellular cues such as metabolic status, nutrient availability, and stress. Studies over decades have unveiled the profound biological significance of this unique protein modification in normal physiology and pathologic processes of diverse cell types or tissues. In hematopoiesis, recent studies have indicated the essential and pleiotropic roles of O-GlcNAcylation in differentiation, proliferation, and function of hematopoietic cells including T cells, B cells, myeloid progenitors, and hematopoietic stem and progenitor cells. Moreover, aberrant O-GlcNAcylation is implicated in the development of hematologic malignancies with dysregulated epigenetics, metabolism, and gene transcription. Thus, it is now recognized that O-GlcNAcylation is one of the key regulators of normal and malignant hematopoiesis.

  • Clinical characteristics of human herpesvirus-6 myelitis after allogeneic hematopoietic stem cell transplantation and its favorable outcome by early intervention

    Shiroshita K., Mori T., Kato J., Sakurai M., Koda Y., Abe R., Murakami K., Sumiya C., Fujita S., Yamaguchi K., Yamazaki R., Nakayama H., Suzuki S., Nakahara J., Okamoto S.

    Bone Marrow Transplantation (Bone Marrow Transplantation)  55 ( 5 ) 939 - 945 2020年05月

    ISSN  02683369

     概要を見る

    After allogeneic hematopoietic stem cell transplantation (HSCT), human herpesvirus-6 (HHV-6) can cause serious central nervous system (CNS) disorder and typically presents as encephalitis. Another manifestation of HHV-6 is myelitis, which has not been fully evaluated. In this study, we retrospectively analyzed 19 patients who developed HHV-6 myelitis after allogeneic HSCT. Median onset was 20 days after transplantation (range, 13–31), with a cumulative incidence of 4.1% at day 40 after transplantation. Median age at transplant was 50 years (range, 17–61). Median copy number of HHV-6 DNA was 3000 copies/ml in cerebrospinal fluid (CSF; range, 200–100,000). The most common symptoms were pruritus, pain of the extremities/back, and numbness. Three patients subsequently developed encephalitis in the clinical course of myelitis; their HHV-6 copy numbers in CSF had been higher than 10,000 copies/ml at the onset of myelitis. Antiviral agents were initiated shortly after onset in all patients, resulting in recovery. These results suggest that myelitis would be an important subtype of HHV-6-associated CNS disorders after allogeneic HSCT, whose prognosis could be favorable by an early intervention. Transplant physicians should recognize early posttransplant neurological symptoms such as pruritus, pain, or numbness as possible signs of HHV-6 myelitis, which could also progress to encephalitis.

  • Efficacy and safety of tyrosine kinase inhibitors for newly diagnosed chronic-phase chronic myeloid leukemia over a 5-year period: results from the Japanese registry obtained by the New TARGET system

    Kizaki M., Takahashi N., Iriyama N., Okamoto S., Ono T., Usui N., Inokuchi K., Nakaseko C., Kurokawa M., Sumi M., Nakamura F., Kawaguchi T., Suzuki R., Yamamoto K., Ohnishi K., Matsumura I., Naoe T., Kizaki M., Mori S., Nemoto T., Sagawa M., Tabayashi T., Tokuhira M., Tomikawa T., Watanabe R., Hatta Y., Inoue Y., Iriyama N., Kobayashi S., Kobayashi Y., Kurita D., Karigane D., Kasahara H., Koda Y., Miyakawa Y., Murakami K., Okamoto S., Watanuki S., Ono T., Nagata Y., Takeshita A., Takahashi N., Kameoka Y., Yoshioka T., Takahashi S., Usui N., Dan K., Inokuchi K., Nakamura K., Abe D., Nakaseko C., Ohwada C., Sakaida E., Shimizu N., Takeuchi M., Arai S., Kogure Y., Koya A., Masamoto Y., Masuda A., Nakazaki K., Toyama K., Hiroshima Y., Ichikawa N., Kirihara T., Kobayashi H., Shimizu I., Sumi M., Ueki T., Hagiwara S., Hirai R., Miwa T., Nakamura F., Nakamura M., Takeshita M., Tanimura A., Hayakawa F., Ishikawa Y., Kiyoi H., Murata M., Tomita A., Kurokawa T., Sugimori C., Arai A., Miura O., Yamamoto M., Imai K., Kobayashi N., Minauchi K., Obara M., Ota S., Ikezoe T., Mori M., Sakai M., Taniguchi A., Togitani K., Hayakawa H., Kajiguchi T., Kamoshita S., Otsuka E.

    International Journal of Hematology (International Journal of Hematology)  109 ( 4 ) 426 - 439 2019年04月

    ISSN  09255710

     概要を見る

    We report the results of a multicenter observational study using the New TARGET system, in which the effectiveness and safety of tyrosine kinase inhibitors (TKIs) were evaluated in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. A total of 506 patients were enrolled between April 2010 and March 2013. Median age was 56 (range 18–92) years; 35% of patients were females. As the first-line therapy, 139 (27.9%), 169 (33.9%) and 144 (28.9%) patients were treated with imatinib, nilotinib, and dasatinib, respectively. Five-year progression-free survival (PFS) and overall survival (OS) were 93.8% and 94.5%, respectively. The OS curve was significantly superior for patients treated with second-generation TKIs than imatinib (P = 0.0068), and an early molecular response (EMR) at 3 months (BCR-ABL1 < 10%) was detected in 328 of 377 patients evaluated for molecular response. The PFS curve was significantly superior for patients with EMR than without (P < 0.0001). Although 12 patients experienced vascular adverse events, no new safety issues were observed in patients with adverse events. The results of this observational study demonstrated that treating newly diagnosed CML-CP patients with TKI results in satisfactory and reliable outcomes.