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Elucidation of pathogenesis of chronic myeloproliferative neoplasms via erythropoietin receptor-binding molecules

Research Project

Project/Area Number 20K07035
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionKeio University

Principal Investigator

Tago Megumi  慶應義塾大学, 薬学部(芝共立), 教授 (30445192)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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)
Keywords慢性骨髄増殖性腫瘍 (MPN) / JAK2V617F変異体 / エリスロポエチン受容体 (EpoR) / STAT5 / CIS / DDX5 / トロンボポエチン受容体 (TpoR) / G-CSF受容体 (G-CSFR) / Rras2 / Pim1 / Pim2
Outline of Research at the Start

慢性骨髄増殖性腫瘍 (MPN) の原因であるチロシンキナーゼJAK2変異体のEpoRを介した発がんシグナルを分子レベルで理解することにより、MPNの発症機序を理解することをめざす。これまでに申請者らは、JAK2変異体が、エリスロポエチン受容体 (EpoR) の3か所のチロシン残基 (Y343, Y460, Y464) のリン酸化を介して、細胞の形質転換や腫瘍形成を誘導することを見出している。本研究では、EpoRの結合分子を同定し、各EpoR結合分子の役割を解析することにより、JAK2変異体の下流で、リン酸化EpoRを基軸として形成される発がんシグナルの実体を解明することをめざす。

Outline of Final Research Achievements

A tyrosine kinase JAK2 mutant (V617F) is the causative gene product of chronic myeloproliferative neoplasia. In this study, we identified CIS as a binding molecule with erythropoietin receptor (EpoR) through the phosphorylation sites of EpoR, which are essential for the transforming ability of the JAK2V617F mutant. We also found that JAK2V617F mutant induces expression of DDX5 via EpoR-STAT5. We demonstrated that CIS functions as an oncogenic suppressor by inhibiting JAK2V617F mutant-induced ERK activation, while DDX5 functions as an oncogenic factor by inducing JAK2V617F mutant-induced mTOR activation.

Academic Significance and Societal Importance of the Research Achievements

現在、JAK2阻害剤Ruxolitinibが慢性骨髄増殖性腫瘍の治療薬として用いられているが、治療効果の低さが問題となっている。本研究により、慢性骨髄増殖性腫瘍におけるCISやDDX5を介した発がん制御機構を解明したことにより、新たな治療標的分子が同定された。よって、本研究成果は慢性骨髄増殖性腫瘍の治療薬開発の一助となると期待される。
また、JAK2V617F変異体は、EpoRを足場タンパク質として、発がん誘導に対して、正にも負にも機能する多様なシグナル経路の活性化を誘導することを見出した。本研究により、複雑なJAK2V617F変異体の発がん誘導機構の一端が解明された。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (25 results)

All 2023 2022 2021 2020

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 11 results) Presentation (13 results) (of which Invited: 1 results)

  • [Journal Article] The indispensable role of the RNA helicase DDX5 in tumorigenesis induced by the myeloproliferative neoplasm-associated JAK2V617F mutant.2023

    • Author(s)
      Takeda K, Tago K, Funakoshi-Tago M.
    • Journal Title

      Cell Signal.

      Volume: 102 Pages: 110537-110537

    • DOI

      10.1016/j.cellsig.2022.110537

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of DDX5 as an indispensable activator of the glucocorticoid receptor in adipocyte differentiation.2023

    • Author(s)
      Hokimoto S, Funakoshi-Tago M, Tago K.
    • Journal Title

      FEBS J.

      Volume: 290 Issue: 4 Pages: 988-1007

    • DOI

      10.1111/febs.16618

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel Mechanism by a Bis-Pyridinium Fullerene Derivative to Induce Apoptosis by Enhancing the MEK-ERK Pathway in a Reactive Oxygen Species-Independent Manner in BCR-ABL-Positive Chronic Myeloid Leukemia-Derived K562 Cells.2022

    • Author(s)
      Sumi K, Tago K, Nakazawa Y, Takahashi K, Ohe T, Mashino T, Funakoshi-Tago M
    • Journal Title

      Int J Mol Sci.

      Volume: 23(2) Issue: 2 Pages: 749-749

    • DOI

      10.3390/ijms23020749

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A bis-pyridinium fullerene derivative induces apoptosis through the generation of ROS in BCR-ABL-positive leukemia cells.2022

    • Author(s)
      Sumi K, Tago K, Nakazawa Y, Takahashi K, Ohe T, Mashino T, Funakoshi-Tago M
    • Journal Title

      Eur J Pharmacol.

      Volume: 916 Pages: 174714-174714

    • DOI

      10.1016/j.ejphar.2021.174714

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The role of MerTK in promoting cell migration is enhanced by the oncogenic Ras/IL-33 signaling axis.2022

    • Author(s)
      Ohta S, Tago K, Kuchimaru T, Funakoshi-Tago M, Horie H, Aoki-Ohmura C, Matsugi J, Yanagisawa K.
    • Journal Title

      FEBS J.

      Volume: 289 Issue: 7 Pages: 1950-1967

    • DOI

      10.1111/febs.16271

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Coffee ingredients, hydroquinone, pyrocatechol, and 4-ethylcatechol exhibit anti-inflammatory activity through inhibiting NF-κB and activating Nrf22022

    • Author(s)
      Funakoshi-Tago M、Matsutaka M, Hokimoto S, Kobata K, Tago K, Tamura H
    • Journal Title

      Journal of Functional Foods

      Volume: 90 Pages: 104980-104980

    • DOI

      10.1016/j.jff.2022.104980

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] EBP2, a novel NPM-ALK-interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53.2021

    • Author(s)
      Uchihara Y, Tago K, Tamura H, Funakoshi-Tago M
    • Journal Title

      Mol Oncol.

      Volume: 15(1) Issue: 1 Pages: 167-194

    • DOI

      10.1002/1878-0261.12822

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The indole-hydantoin derivative exhibits anti-inflammatory activity by preventing the transactivation of NF-κB through the inhibition of NF-κB p65 phosphorylation at Ser276.2021

    • Author(s)
      Lin X, Tago K, Okazaki N, So T, Takahashi K, Mashino T, Tamura H, Funakoshi-Tago M
    • Journal Title

      Int Immunopharmacol.

      Volume: 100 Pages: 108092-108092

    • DOI

      10.1016/j.intimp.2021.108092

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] K15 promoter-driven enforced expression of NKIRAS exhibits tumor suppressive activity against the development of DMBA/TPA-induced skin tumors.2021

    • Author(s)
      Tago K, Ohta S, Aoki-Ohmura C, Funakoshi-Tago M, Sashikawa M, Matsui T, Miyamoto Y, Wada T, Oshio T, Komine M, Matsugi J, Furukawa Y, Ohtsuki M, Yamauchi J, Yanagisawa K
    • Journal Title

      Sci Rep.

      Volume: 11(1) Issue: 1 Pages: 20658-20658

    • DOI

      10.1038/s41598-021-00200-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Coffee decoction enhances tamoxifen proapoptotic activity on MCF-7 cells.2020

    • Author(s)
      Funakoshi-Tago M, Tago K, Li C, Hokimoto S, Tamura H.
    • Journal Title

      Sci Rep.

      Volume: 10(1) Issue: 1 Pages: 19588-19588

    • DOI

      10.1038/s41598-020-76445-z

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kampo medicines, Rokumigan, Hachimijiogan, and Goshajinkigan, significantly inhibit glucagon-induced CREB activation.2020

    • Author(s)
      Funakoshi-Tago M, Yu S, Kushida A, Takeuchi K, Tamura H.
    • Journal Title

      Heliyon.

      Volume: 6(3) Issue: 3 Pages: e03598-e03598

    • DOI

      10.1016/j.heliyon.2020.e03598

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pyrocatechol, a component of coffee, suppresses LPS-induced inflammatory responses by inhibiting NF-κB and activating Nrf2.2020

    • Author(s)
      Funakoshi-Tago M, Nonaka Y, Tago K, Takeda M, Ishihara Y, Sakai A, Matsutaka M, Kobata K, Tamura H.
    • Journal Title

      Sci. Rep.

      Volume: 10 Issue: 1 Pages: 2584-2584

    • DOI

      10.1038/s41598-020-59380-x

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 慢性骨髄増殖性腫瘍の原因遺伝子産物JAK2V617F変異体の発がん誘導機構2023

    • Author(s)
      多胡 めぐみ
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Annual Research Report
  • [Presentation] MPN原因遺伝子産物JAK2V617F変異体によるDDX5を介した発がん誘導2023

    • Author(s)
      武田 健吾、多胡 憲治、上田 史仁、多胡 めぐみ
    • Organizer
      日本薬学会第143年会(札幌)
    • Related Report
      2022 Annual Research Report
  • [Presentation] 融合型チロシンキナーゼNPM-ALKによる発がん誘導におけるSTAT3のアセチル化の機能解析2022

    • Author(s)
      向來 朗、林 昕、 多胡 憲治、多胡 めぐみ
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] エリスロポエチンによるSTAT5非依存的な細胞増殖誘導の分子機構の解析2022

    • Author(s)
      武田健吾、多胡憲治、上田史仁、多胡めぐみ
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 慢性骨髄増殖性腫瘍の原因遺伝子産物 JAK2V617F 変異体による RNA ヘリカーゼDDX5 を介した形質転換メカニズムの解析2022

    • Author(s)
      武田健吾、多胡憲治、上田史仁、多胡めぐみ
    • Organizer
      第 22 回 Pharmaco-Hematology シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 慢性骨髄増殖性腫瘍における RNA ヘリカーゼDDX5 を介した発がん誘導機構2022

    • Author(s)
      武田健吾、多胡憲治、多胡めぐみ
    • Organizer
      2022 年度日本生化学会関東支部例会
    • Related Report
      2022 Annual Research Report
  • [Presentation] JAK2V617F 変異体による DDX5 を介した形質転換の分子メカニズムの解析2021

    • Author(s)
      武田健吾、多胡憲治、上田史仁、多胡めぐみ
    • Organizer
      2021 年度 日本生化学会関東支部例会
    • Related Report
      2021 Research-status Report
  • [Presentation] 未分化大細胞リンパ腫におけるNPM-ALKによるSTAT5の発現抑制機構2021

    • Author(s)
      向来朗、 戸田恵里花、 Lin Xin、 上田史仁、 多胡めぐみ
    • Organizer
      65回日日本薬学会関東支部大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 融合型チロシンキナーゼNPM-ALKによるSTAT3を介した発がん誘導機構2021

    • Author(s)
      Lin Xin、 上田史仁、 多胡憲治、 多胡めぐみ
    • Organizer
      65回日日本薬学会関東支部大会
    • Related Report
      2021 Research-status Report
  • [Presentation] JAK2V617F変異体によるG-CSF受容体を介した発がん誘導シグナル2021

    • Author(s)
      迫ゆうか、 片野響、 上田史仁、 多胡めぐみ
    • Organizer
      65回日日本薬学会関東支部大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 認知症予防と炎症応答の調節-コーヒーによる抗炎症作用-2021

    • Author(s)
      多胡めぐみ
    • Organizer
      第10回 日本認知症予防学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] JAK2V617F変異体による腫瘍形成に及ぼすDDX5の役割2021

    • Author(s)
      武田 健吾、仲本 眞子、多胡 憲治、上田 史仁、多胡 めぐみ
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] NPM-ALK発現ALCLにおけるメトトレキサートによるアポトーシス誘導機構2021

    • Author(s)
      芳谷 郁実、初田 航一、内原 脩貴、多胡 憲治、多胡 めぐみ
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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