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Elucidation of the molecular pathogenesis of myeloproliferative neoplasms with CALR mutations for the development of novel therapeutic strategies.

Research Project

Project/Area Number 19K07880
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52010:General internal medicine-related
Research InstitutionKawasaki Medical School

Principal Investigator

Kitanaka Akira  川崎医科大学, 医学部, 教授 (70343308)

Co-Investigator(Kenkyū-buntansha) 通山 薫  川崎医科大学, 医学部, 教授 (80227561)
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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords骨髄増殖性腫瘍 / calreticulin / チロシンキナーゼ / Calreticulin / MPL
Outline of Research at the Start

骨髄増殖性腫瘍(MPN)は、サイトカイン受容体シグナル伝達系の恒常的な活性化を引き起こす遺伝子変異によって発症する。近年、JAK2に次いでMPN症例に変異が多い遺伝子としてCALRが見いだされたが、その発症メカニズムについては不明な点が多い。本研究では、変異CALRのタンパク合成から輸送、MPLとの結合までを含んだいずれかの過程を阻害する化合物を見いだすことによって、MPNの病態形成に重要な分子を抽出し、得られた知見をもとに新たな治療法の開発を目指す。

Outline of Final Research Achievements

In this study, we attempted to identify key molecules in the intracellular signaling mechanism by which mutant CALR activates MPL-mediated signaling. We found that the Src-selective inhibitor PP2 and the Bcr-Abl/Src inhibitor bosutinib suppressed the proliferation of F-36P-MPL cells expressing CALR mutant and decreased the transcriptional activity of STAT5, which was enhanced by the expression of mutated CALR, in 293T cells. Of note, bosutinib inhibited cell proliferation at clinically achievable concentrations. Specific supression of Lyn, a major Src family member in hematopoietic cells, inhibited mutant CALR-dependent cell proliferation, indicating that Lyn may play an important role in the signaling mechanism by mutant CALR.

Academic Significance and Societal Importance of the Research Achievements

近年、骨髄増殖性腫瘍(MPN)の病態解明が著しく進歩し、病因となる変異遺伝子産物を標的とした新規薬剤JAK阻害薬が臨床応用されている。JAK阻害薬はMPN症例の多くに変異が認められるJAK2を標的としており、臨床症状の改善に有効であるが、血球減少の副作用がある。疾患の発症・進展に関与する変異型JAK2と、正常な造血の維持に必要な野生型JAK2の間で酵素活性を有する部分の構造に差異はなく、両者に異なった作用を示す阻害薬の開発は極めて困難である。本研究で見出した変異CALR下流分子の詳細を解明することは、これまでと異なった作用機序のMPN治療薬開発につながる可能性がある。

Report

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

    (20 results)

All 2022 2021 2020 2019

All Journal Article (12 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (5 results) (of which Invited: 3 results) Book (3 results)

  • [Journal Article] Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma2022

    • Author(s)
      Kameda T, Shide K, Tahira Y, Sekine M, Sato S, Ishizaki J, Takeuchi M, Akizuki K, Kamiunten A, Shimoda H, Toyama T, Maeda K, Yamashita K, Kawano N, Kawano H, Hidaka T, Yamaguchi H, Kubuki Y, Kitanaka A, Matsuoka H, Shimoda K
    • Journal Title

      Viruses

      Volume: 14 Issue: 4 Pages: 710-710

    • DOI

      10.3390/v14040710

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [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] Whole-genome landscape of adult T-cell leukemia/lymphoma2022

    • Author(s)
      Kogure Y, Kameda T, Koya J, Yoshimitsu M, Nosaka K, Yasunaga JI, Imaizumi Y, Watanabe M, Saito Y, Okada A, Kakiuchi N, Nannya Y,Kitanaka A, Hidaka M, Nakano N, Utsunomiya A, Sica RA, Acuna-Villaorduna A, Janakiram M, Shah U, Shibata T, Takeuchi K, Ogawa S, Ye BH, Shimoda K, Kataoka K(他20名、26番目)
    • Journal Title

      Blood

      Volume: 139 Issue: 7 Pages: 967-982

    • DOI

      10.1182/blood.2021013568

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-12021

    • Author(s)
      Koya J, Saito Y, Kameda T, Kogure Y, Yuasa M, Nagasaki J, McClure MB, Shingaki S, Tabata M, Tahira Y, Akizuki K, Kamiunten A, Sekine M, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Nakano N, Utsunomiya A, Togashi Y, Ogawa S, Shimoda K, Kataoka K
    • Journal Title

      Blood Cancer Discovery

      Volume: 2 Issue: 5 Pages: 450-467

    • DOI

      10.1158/2643-3230.bcd-21-0044

    • NAID

      120007145001

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] VLX1570 induces apoptosis through the generation of ROS and induction of ER stress on leukemia cell lines2021

    • Author(s)
      Kurozumi N, Tsujioka T, Ouchida M, Sakakibara K, Nakahara T, Suemori SI, Takeuchi M, Kitanaka A, Shibakura M, Tohyama K
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 8 Pages: 3302-3313

    • DOI

      10.1111/cas.14982

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between microRNA-527 and glypican-3 in hepatocellular carcinoma2021

    • Author(s)
      Nomura K, Kitanaka A, Iwama H, Tani J, Nomura T, Nakahara M, Ohura K, Tadokoro T, Fujita K, Mimura S, Yoneyama H, Kobara H, Morishita A, Okano K, Suzuki Y, Tsutsi K, Himoto T, Masaki T
    • Journal Title

      Oncology Letters

      Volume: 21 Issue: 3 Pages: 229-229

    • DOI

      10.3892/ol.2021.12490

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Higher average chemotherapy dose intensity improves prognosis in patients with aggressive adult T‐cell leukemia/lymphoma2020

    • Author(s)
      Sekine M, Kameda T, Shide K, Maeda K, Toyama T, Kawano N, Takeuchi M, Kawano H, Sato S, Ishizaki J, Kukita T, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Hidaka T, Yamashita K, Matsuoka H, Kitanaka A, Kubuki Y, Shimoda K
    • Journal Title

      European Journal of Haematology

      Volume: 106 Issue: 3 Pages: 398-407

    • DOI

      10.1111/ejh.13565

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma2020

    • Author(s)
      Nakahata S, Syahrul C, Nakatake A, Sakamoto K, Yoshihama M, Nishikata I, Ukai Y, Matsuura T, Kameda T, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Ito A, Takemoto S, Nakano N, Saito M, Iwanaga M, Sagara Y, Mochida K, Amano M, Maeda K, Sueoka E, Okayama A, Utsunomiya A, Shimoda K, Watanabe T, Morishita K
    • Journal Title

      Haematologica

      Volume: 106 Pages: 532-542

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] 骨髄系腫瘍の臨床 慢性骨髄性白血病 移行期・急性転化期の慢性骨髄性白血病の病因・病態と治療2020

    • Author(s)
      北中 明
    • Journal Title

      日本臨床

      Volume: 8 Pages: 328-334

    • Related Report
      2020 Research-status Report
  • [Journal Article] 細胞形態の特徴から診断し得た病初期の急性前骨髄球性白血病の1症例2020

    • Author(s)
      小林 美紀, 大倉 貢, 向井 祐子, 勝原 祐香里, 安福 明子, 通山 薫, 北中 明
    • Journal Title

      日本検査血液学会雑誌

      Volume: 21 Pages: 207-213

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] 造血器腫瘍のWHO分類改訂第4版(2017年)のポイント 骨髄系腫瘍2020

    • Author(s)
      北中 明
    • Journal Title

      臨床病理

      Volume: 68 Pages: 139-145

    • Related Report
      2019 Research-status Report
  • [Journal Article] Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway.2019

    • Author(s)
      Sakakibara K, Tsujioka T, Kida JI, Kurozumi N, Nakahara T, Suemori SI, Kitanaka A, Arao Y, Tohyama K
    • Journal Title

      International journal of hematology

      Volume: 110 Issue: 2 Pages: 213-227

    • DOI

      10.1007/s12185-019-02667-1

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Srcチロシンキナーゼ抑制によるCALR変異を有する骨髄増殖性腫瘍の増殖抑制2019

    • Author(s)
      木田潤一郎, 榊原佳奈枝, 辻岡貴之, 末盛晋一郎, 下田和哉, 通山 薫, 北中 明
    • Organizer
      第66回日本臨床検査医学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] ヒト白血病細胞株における新規MEK1/2阻害剤ビニメチニブの効果2019

    • Author(s)
      榊原佳奈枝, 辻岡貴之, 木田潤一郎, 中原貴子, 末盛晋一郎, 北中 明, 荒尾雄二郎, 通山 薫
    • Organizer
      第66回日本臨床検査医学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 血器腫瘍のWHO分類改訂第4版(2017)のポイント 骨髄系腫瘍2019

    • Author(s)
      北中 明
    • Organizer
      第66回日本臨床検査医学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 検体系検査のパニック値を巡る諸問題2019

    • Author(s)
      北中 明
    • Organizer
      第66回日本臨床検査医学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 血液形態診断のためのケースカンファレンス 前立腺癌治療中の好中球減少2019

    • Author(s)
      小林美紀, 大倉 貢, 向井祐子, 勝原祐香里, 安福明子, 北中 明, 通山 薫
    • Organizer
      第66回日本臨床検査医学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] スタンダード検査血液学 第4版2021

    • Author(s)
      北中明(部分執筆)
    • Total Pages
      552
    • Publisher
      医歯薬出版株式会社
    • ISBN
      9784263226919
    • Related Report
      2021 Annual Research Report
  • [Book] 今日の治療指針 2020年版2020

    • Author(s)
      福井 次矢
    • Total Pages
      2115
    • Publisher
      医学書院
    • ISBN
      9784260039390
    • Related Report
      2020 Research-status Report
  • [Book] 血液疾患最新の治療2020-20222019

    • Author(s)
      北中 明, 通山 薫 部分執筆
    • Total Pages
      390
    • Publisher
      南江堂
    • ISBN
      9784524249787
    • Related Report
      2019 Research-status Report

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

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