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Control of myelofibrosis targeting the amplification mechanism of CALR mutant stem cells and the functional motif of CALR mutant proteins

Research Project

Project/Area Number 19K08819
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionUniversity of Miyazaki

Principal Investigator

Shide Kotaro  宮崎大学, 医学部, 助教 (20468028)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords骨髄増殖性腫瘍 / 原発性骨髄線維症 / 造血幹細胞 / 分子標的療法 / Calreticulin
Outline of Research at the Start

骨髄線維症患者の5年生存率は40%と予後不良である。この疾患群のドライバー変異であるcalreticulin(CALR)の変異は造血幹細胞レベルで生じており、約3割の患者にみられる。本研究では、申請者が見出した同変異に関する最新の研究成果を基盤として、「CALR変異造血幹細胞のクローン拡大機序」、「CALR変異蛋白による増殖シグナル活性化機序」を解明する。更に、両機序を標的とした病態制御のproof of conceptを得て、骨髄線維症の革新的治療に道を開くことを目標とする。

Outline of Final Research Achievements

We created the first blood cell-specific Calreticulin (Calr) KO mouse that had not yet been developed, and clarified the role of Calr in hematopoiesis. We further showed that haploinsufficiency of the Calr gene enhances the competitive repopulation capacity of hematopoietic stem cells (HSCs), and also enhances the clonal expansion of HSCs with CALR mutations in myeloproliferative patients.
Regarding the mechanism of cell proliferation by CALR mutant protein, we found a sequence essential for tumorigenicity in vitro and in vivo in the amino acid sequence specific to the mutant protein. We plan to begin preclinical studies targeting these amino acids.

Academic Significance and Societal Importance of the Research Achievements

原発性骨髄線維症(primary myelofibrosis:PMF) 、および本態性血小板血症(essential thrombocythemia:ET)に続発する二次性骨髄線維症(post-ET MF)患者の5年生存率は40%と予後不良であり、PMF, post-ET MFには臨床的なunmet needsがある。この疾患群のドライバー変異であるcalreticulin(CALR)の変異は造血幹細胞レベルで生じており、約3割の患者にみられる。本研究の成果は、CALR変異が疾患を引き起こす仕組みを明らかにしたものであり、これらの患者群を対象とした新規治療開発の基盤となるものである。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (32 results)

All 2022 2021 2020 2019

All Journal Article (17 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 13 results,  Open Access: 12 results) Presentation (15 results) (of which Int'l Joint Research: 4 results,  Invited: 3 results)

  • [Journal Article] Immunohistopathological Analysis of Extramedullary Hematopoiesis and Angiogenesis of Spleen in a Case of Primary Myelofibrosis with Huge Splenomegaly2022

    • Author(s)
      Kawano N, Saito N, Yoshida S, Kitanaka A, Shide K, Marutsuka K, Ohshima K, Shimoda K
    • Journal Title

      The Tohoku Journal of Experimental Medicine

      Volume: 256 Issue: 2 Pages: 119-125

    • DOI

      10.1620/tjem.256.119

    • NAID

      130008160463

    • ISSN
      0040-8727, 1349-3329
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils2021

    • Author(s)
      Kimishima Yusuke、Misaka Tomofumi、Yokokawa Tetsuro、Wada Kento、Ueda Koki、Sugimoto Koichi、Minakawa Keiji、Nakazato Kazuhiko、Ishida Takafumi、Oshima Motohiko、Koide Shuhei、Shide Kotaro、Shimoda Kazuya、Iwama Atsushi、Ikeda Kazuhiko、Takeishi Yasuchika
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 6177-6177

    • DOI

      10.1038/s41467-021-26435-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fibrocytes in primary myelofibrosis2021

    • Author(s)
      Kazuya Shimoda, Yoshinori Ozono, Kotaro Shide
    • Journal Title

      Oncotarget

      Volume: 12 Issue: 20 Pages: 2101-2103

    • DOI

      10.18632/oncotarget.27971

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Calreticulin mutations in myeloproliferative neoplasms2021

    • Author(s)
      Kotaro Shide
    • Journal Title

      Int Rev Cell Mol Biol

      Volume: 365 Pages: 179-226

    • DOI

      10.1016/bs.ircmb.2021.05.005

    • ISBN
      9780323899390
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pathophysiology of myeloproliferative neoplasms revealed from mouse models with driver mutations.2020

    • Author(s)
      幣 光太郎
    • Journal Title

      Cytometry Research

      Volume: 30 Issue: 2 Pages: 15-20

    • DOI

      10.18947/cytometryresearch.30.2_15

    • NAID

      130007952539

    • ISSN
      0916-6920, 2424-0664
    • Year and Date
      2020-12-11
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Calreticulin haploinsufficiency augments stem cell activity and is required for onset of myeloproliferative neoplasms2020

    • Author(s)
      Shide Kotaro、Kameda Takuro、Kamiunten Ayako、Ozono Yoshinori、Tahira Yuki、Yokomizo-Nakano Takako、Kubota Sho、Ono Masaya、Ikeda Kazuhiko、Sekine Masaaki、Akizuki Keiichi、Nakamura Kenichi、Hidaka Tomonori、Kubuki Yoko、Iwakiri Hisayoshi、Hasuike Satoru、Nagata Kenji、Sashida Goro、Shimoda Kazuya
    • Journal Title

      Blood

      Volume: - Pages: 106-118

    • DOI

      10.1182/blood.2019003358

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neoplastic fibrocytes play an essential role in bone marrow fibrosis in Jak2V617F-induced primary myelofibrosis mice2020

    • Author(s)
      Ozono Yoshinori、Shide Kotaro、Kameda Takuro、Kamiunten Ayako、Tahira Yuki、Sekine Masaaki、Akizuki Keiichi、Nakamura Kenichi、Iwakiri Hisayoshi、Sueta Mitsue、Hidaka Tomonori、Kubuki Yoko、Yamamoto Shojiro、Hasuike Satoru、Sawaguchi Akira、Nagata Kenji、Shimoda Kazuya
    • Journal Title

      Leukemia

      Volume: - Issue: 2 Pages: 454-467

    • DOI

      10.1038/s41375-020-0880-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] JAK2-negative acute monocytic leukemia with TET2 mutation in essential thrombocythemia with JAK2 mutation with literature review2020

    • Author(s)
      Ogasawara Toshie、Kawauchi Kiyotaka、Ono Takuya、Marshall Shoko、Shide Kotaro、Shimoda Kazuya、Mori Naoki、Sakura Hiroshi
    • Journal Title

      Leukemia Research Reports

      Volume: 13 Pages: 100194-100194

    • DOI

      10.1016/j.lrr.2019.100194

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The role of driver mutations in myeloproliferative neoplasms: insights from mouse models2020

    • Author(s)
      Kotaro Shide
    • Journal Title

      International Journal of Hematology

      Volume: 111 Issue: 2 Pages: 206-216

    • DOI

      10.1007/s12185-019-02803-x

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] TP53 and PTEN Mutations Were Shared in Concurrent Germ Cell Tumor and Acute Megakaryoblastic Leukemia2020

    • Author(s)
      Keiichi Akizuki, Masaaki Sekine, Yasunori Kogure, Takuro Kameda, Kotaro Shide, Junji Koya, Ayako Kamiunten, Yoko Kubuki, Yuki Tahira, Tomonori Hidaka, Takumi Kiwaki, Hiroyuki Tanaka, Yuichiro Sato, Hiroaki Kataoka, Keisuke Kataoka & Kazuya Shimoda
    • Journal Title

      BMC Cancer

      Volume: 20 Issue: 1 Pages: 5-5

    • DOI

      10.1186/s12885-019-6497-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Essential thrombocytosis attributed to JAK2-T875N germline mutation2019

    • Author(s)
      Makoto Yoshimitsu, Miho Hachiman, Yuichiro Uchida, Naosuke Arima, Akihiko Arai, Yuhei Kamada, Kotaro Shide, Masafumi Ito, Kazuya Shimoda, Kenji Ishitsuka
    • Journal Title

      International Journal of Hematology

      Volume: 110 Issue: 5 Pages: 584-590

    • DOI

      10.1007/s12185-019-02725-8

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Monocyte-derived fibrocytes elimination had little contribution on liver fibrosis2019

    • Author(s)
      Ozono Yoshinori、Shide Kotaro、Toyoshima Fumiyo、Takaishi Yuuka、Tsuchimochi Mai、Kamiunten Ayako、Kameda Takuro、Nakamura Kenichi、Miike Tadashi、Kusumoto Kazunori、Iwakiri Hisayoshi、Hasuike Satoru、Nagata Kenji、Sawaguchi Akira、Shimoda Kazuya
    • Journal Title

      Hepatobiliary & Pancreatic Diseases International

      Volume: Epub ahead of print Issue: 4 Pages: 348-353

    • DOI

      10.1016/j.hbpd.2019.02.002

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Vitamin D receptor?mediated skewed differentiation of macrophages initiates myelofibrosis and subsequent osteosclerosis2019

    • Author(s)
      Wakahashi Kanako、Minagawa Kentaro、Kawano Yuko、Kawano Hiroki、Suzuki Tomohide、Ishii Shinichi、Sada Akiko、Asada Noboru、Sato Mari、Kato Shigeaki、Shide Kotaro、Shimoda Kazuya、Matsui Toshimitsu、Katayama Yoshio
    • Journal Title

      Blood

      Volume: 133 Issue: 15 Pages: 1619-1629

    • DOI

      10.1182/blood-2018-09-876615

    • NAID

      120007002632

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CALR変異によるMPN発症機構2019

    • Author(s)
      幣光太郎
    • Journal Title

      血液内科

      Volume: 78 Pages: 678-674

    • NAID

      40021930128

    • Related Report
      2019 Research-status Report
  • [Journal Article] 骨髄増殖性腫瘍におけるJAK阻害薬の使用基準2019

    • Author(s)
      3.幣光太郎, 下田和哉
    • Journal Title

      血液内科

      Volume: 78 Pages: 870-876

    • NAID

      40021948459

    • Related Report
      2019 Research-status Report
  • [Journal Article] マウスモデルによるMPNの病態解析2019

    • Author(s)
      幣光太郎
    • Journal Title

      血液内科

      Volume: 79 Pages: 542-549

    • Related Report
      2019 Research-status Report
  • [Journal Article] 骨髄増殖性腫瘍の病期進展メカニズム2019

    • Author(s)
      幣光太郎, 下田和哉
    • Journal Title

      血液内科

      Volume: 79 Pages: 697-701

    • Related Report
      2019 Research-status Report
  • [Presentation] Role of driver mutations revealed from MPN mouse models.2021

    • Author(s)
      Kotaro Shide
    • Organizer
      The 12th JSH International Symposium 2021 in Kamaura, AS II-3, Kamakura JAPAN (WEB併用)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Hematopoietic cells with MPN driver mutations promote pulmonary hypertension2021

    • Author(s)
      Kazuhiko Ikeda,Tomofumi Misaka,Yusuke Kimishima, Tetsuro Yokokawa,Keiji Minakawa,Koki Ueda,Motohiko Oshima, Shuhei Koide,Kotaro Shide,Kazuya Shimoda,Osamu Nakajima, Atsushi Iwama,Yasuchika Takeishi
    • Organizer
      The 83th Annual Meeting of the Japanese society of Hematology, OS2-7A-14, Sendai JAPAN, Sep 24.2021 (口演)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Loss of EZH2 does not affect the severity of murine myeloproliferative neoplasms with CALR mutation2021

    • Author(s)
      Ayako Kamiunten, Yuki Tahira, Keiichi Akizuki, Masaaki Sekine, Takuro Kameda, Kotaro Shide, Tomonori Hidaka, Yoko Kubuki, Kazuya Shimoda
    • Organizer
      The 83th Annual Meeting of the Japanese society of Hematology, OS2-7A-3, Sendai JAPAN, Sep 24.2021 (口演)
    • Related Report
      2021 Annual Research Report
  • [Presentation] RNA splicing machinery gene mutations in patients with myeloproliferative neoplasms (MPNs) in Japan2021

    • Author(s)
      Kotaro Shide, Saki Ogawa, Ayako Kamiunten et al.
    • Organizer
      The 83th Annual Meeting of the Japanese society of Hematology, OS2-7B-4, Sendai JAPAN, Sep 24.2021 (口演)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Renal impairment associated with myeloproliferative neoplasm (MPN)2021

    • Author(s)
      Yuki Tahira, Kotaro Shide, Ayako Kamiunten, Takuro Kameda, Keiichi Akizuki, Masaaki Sekine, Tomonori Hidaka, Yoko Kubuki, Kazuya Shimoda
    • Organizer
      The 83th Annual Meeting of the Japanese society of Hematology, PS-11-6, Sendai JAPAN, Sep 23.2021 (ポスター)
    • Related Report
      2021 Annual Research Report
  • [Presentation] はじめての血液学2 、血球増加症へのアプローチ2020

    • Author(s)
      Kotaro Shide
    • Organizer
      The 82th Annual Meeting of the Japanese society of Hematology, SN-2, Kyoto JAPAN (WEB開催), Oct 10.2020 (教育講演)
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Mechanism of enhanced IL1α production induced by JAK2V617F2020

    • Author(s)
      Kotaro Shide,Ayako Kamiunten,Yoshinori Ozono,Takuro Kameda,Yuki Tahira,Keiichi Akizuki,Masaaki Sekine,Tomonori Hidaka,Yoko Kubuki,Kazuya Shimoda
    • Organizer
      The 82th Annual Meeting of the Japanese society of Hematology, OS-25-5, Kyoto JAPAN (WEB開催), Oct 10.2020 (口演)
    • Related Report
      2020 Research-status Report
  • [Presentation] Myeloproliferative neoplasm (MPN) nephropathy in a Jak2V617F induced MPN mouse model2020

    • Author(s)
      Yuki Tahira,Kotaro Shide,Yoshinori Ozono,Ayako Kamiunten,Takuro Kameda,Keiichi Akizuki,Masaaki Sekine,Tomonori Hidaka,Yoko Kubuki,Kazuya Shimoda
    • Organizer
      The 82th Annual Meeting of the Japanese society of Hematology, PS-12-6, Kyoto JAPAN (WEB開催), Oct 10.2020 (ポスター)
    • Related Report
      2020 Research-status Report
  • [Presentation] SRSF2, U2AF1, and IDH mutations in patients with myeloproliferative neoplasms (MPNs) in Japan2020

    • Author(s)
      Ogawa S, Shide K, Kamiunten A, Kubuki Y, Takeuchi M, Matsue K, Shimomura T, Suzushima H, Kawano N, Yamashita K, Yasumi M, Karasuno T, Imataki O, Kadowaki N, Yonezawa A, Otsuka E, Hidaka T, Kameda T, Akizuki K, Sekine M, Tahira Y, Shimoda K
    • Organizer
      The 82th Annual Meeting of the Japanese society of Hematology, OS-27-4, Kyoto JAPAN (WEB開催), Oct 10.2020 (口演)
    • Related Report
      2020 Research-status Report
  • [Presentation] A case of 5q deletion syndrome with CALR mutation2020

    • Author(s)
      Shiho Fujiwara,Kotaro Shide,Kazuya Shimoda,Nobuyuki Arima,Yukiko Kimura,Yuko Watanabe,Taizo Shimomura,Hitoshi Suzushima
    • Organizer
      The 82th Annual Meeting of the Japanese society of Hematology, PS-15-10, Kyoto JAPAN (WEB開催), Oct 10.2020 (ポスター)
    • Related Report
      2020 Research-status Report
  • [Presentation] Clonal Hematopoiesis With JAK2V617F Promotes Pulmonary Hypertension Through ALK12020

    • Author(s)
      Yusuke Kirishima, Tomofumi Misaka, Tetsuro Yokokawa, Kento Wada, Koki Ueda, Koichi Sugimoto, Keiji Minakawa, Kazuhiko Nakazato, Takafumi Ishida, Motohiko Oshima, Shuhei Koide, Kotaro Shide, Kazuya Shimoda, Atsushi Iwama, Kazuhiko Ikeda, Yasuchika Takeishi
    • Organizer
      American Heart Association Scientific Session 2020, abstract 12873
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] The Role of Calreticulin in Normal Hematopoiesis and Neoplastic Hematopoiesis of Myeloproliferative Neoplasms2019

    • Author(s)
      Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Yoshinori Ozono, Yuki Tahira, Masaaki Sekine, Masaya Ono, Takako Yokomizo, Sho Kubota, Keiichi Akizuki, Yoko Kubuki, Tomonori Hidaka, Goro Sashida, Kazuya Shimoda
    • Organizer
      American Society of Hematology the 61st Annual Meeting and Exposition
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Depletion of Neoplastic CD11b Positive Cells in Jak2V617F Mutant Mice Reduced Fibrocytes in Bone Marrow and Improved Myelofibrosis2019

    • Author(s)
      Yoshinori Ozono, Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Yuki Tahira, Masaaki Sekine, Keiichi Akizuki, Kenichi Nakamura, Hisayoshi Iwakiri, Tomonori Hidaka, Yoko Kubuki, Satoru Hasuike, Fumiyo Toyoshima, Akira Sawaguchi, Kenji Nagata, Kazuya Shimoda
    • Organizer
      American Society of Hematology the 61st Annual Meeting and Exposition
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Calreticulin不全が造血系に与える影響2019

    • Author(s)
      幣光太郎、亀田拓郎、上運天綾子、大園芳徳、尾野雅哉、横溝貴子、久保田翔、田平優貴、秋月渓一、関根雅明、久冨木庸子、日高智徳、指田吾郎、伊川正人、下田和哉
    • Organizer
      The 81th Annual Meeting of the Japanese society of Hematology
    • Related Report
      2019 Research-status Report
  • [Presentation] マウスモデルを用いた骨髄増殖性腫瘍発症機構の解析2019

    • Author(s)
      幣 光太郎
    • Organizer
      第29回日本サイトメトリー学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited

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Published: 2019-04-18   Modified: 2023-01-30  

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