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Development of therapeutic strategies targeting molecular mechanisms underlying the therapy resistance endowed by activated tyrosine kinase mutants in hematological malignancies

Research Project

Project/Area Number 15K09467
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

MIURA Osamu  東京医科歯科大学, 大学院医歯学総合研究科, 主任教授 (10209710)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords血液腫瘍学 / 白血病 / 分子標的療法 / チロシンキナーゼ / FLT3-ITD / JAK2-V617F / BCR/ABL / 造血器腫瘍
Outline of Final Research Achievements

Constitutively activated aberrant tyrosine kinases play important roles in development and evolution of hematopoietic malignancies and are also implicated in acquisition of therapy resistance. In the present studies we found that Pim kinases induced through the robust activation of STAT5 by FLT3-ITD protect the mTORC1/4EBP1/Mcl-1 pathway to confer the resistance to the PI3K/Akt inhibitors on FLT3-ITD-positive acute myeloid leukemia cells and, thus, represent promising therapeutic targets. We also found that, by augmenting p53-mediated downregulation of Chk1, the Mdm2 inhibitors enhances apoptosis induced in leukemic cells synergistically by chemotherapeutics and inhibitors for aberrant tyrosine kinases, which also downregulate Chk1 activation. Finally, we demonstrated that PECAM-1 enhanced CXCR4-mediated SDF-1-signaling in hematopoietic cells by binding with CXCR4 to maintain its surface expression in a similar manner with the CXCR4 mutants found in hematopoietic malignancies.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (19 results)

All 2018 2017 2016 2015

All Journal Article (7 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 7 results,  Open Access: 6 results,  Acknowledgement Compliant: 2 results) Presentation (12 results)

  • [Journal Article] FLT3-ITD induces expression of Pim kinases through STAT5 to confer resistance to the PI3K/Akt pathway inhibitors on leukemic cells by enhancing the mTORC1/Mcl-1 pathway2018

    • Author(s)
      Okada Keigo、Nogami Ayako、Ishida Shinya、Akiyama Hiroki、Chen Cheng、Umezawa Yoshihiro、Miura Osamu
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 10 Pages: 8870-86

    • DOI

      10.18632/oncotarget.22926

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular mechanisms for enhancement of stromal cell-derived factor 1?induced chemotaxis by platelet endothelial cell adhesion molecule 1 (PECAM-1)2017

    • Author(s)
      Umezawa Yoshihiro、Akiyama Hiroki、Okada Keigo、Ishida Shinya、Nogami Ayako、Oshikawa Gaku、Kurosu Tetsuya、Miura Osamu
    • Journal Title

      Journal of Biological Chemistry

      Volume: 292 Issue: 48 Pages: 19639-19655

    • DOI

      10.1074/jbc.m117.779603

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Acute myeloid leukemia with t(3;21)(q26.2;q22) developing following low‐dose methotrexate therapy for rheumatoid arthritis and expressing two AML1/MDS1/EVI1 fusion proteins: A case report2017

    • Author(s)
      KEISUKE TANAKA, GAKU OSHIKAWA, HIROKI AKIYAMA, SHINYA ISHIDA, TOSHIKAGE NAGAO, MASAHIDE YAMAMOTO and OSAMU MIURA
    • Journal Title

      ONCOLOGY LETTERS

      Volume: 印刷中

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Down regulation of Chk1 by p53 plays a role in synergistic induction of apoptosis by chemotherapeutics and inhibitors for Jak2 or BCR/ABL in hematopoietic cells2016

    • Author(s)
      Umezawa Y, Kurosu T, Akiyama H, Wu N, Nogami A, Nagao T and Miura O
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 28 Pages: 44448-44461

    • DOI

      10.18632/oncotarget.9844

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] FLT3-ITD confers resistance to the PI3K/Akt pathway inhibitors by protecting the mTOR/4EBP1/Mcl-1 pathway through STAT5 activation in acute myeloid leukemia2015

    • Author(s)
      Nogami A, Oshikawa G, Okada K, Fukutake S, Umezawa Y, Nagao T, Kurosu T and Miura O
    • Journal Title

      Oncotarget

      Volume: 6 Pages: 9189-205

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A novel MYD88 mutation, L265RPP, in Waldenstrom macroglobulinemia activates the NF-kappaB pathway to upregulate Bcl-xL expression and enhances cell survival2015

    • Author(s)
      Nagao T, Oshikawa G, Ishida S, Akiyama H, Umezawa Y, Nogami A, Kurosu T and Miura O
    • Journal Title

      Blood cancer journal

      Volume: 5 Issue: 5 Pages: 315-317

    • DOI

      10.1038/bcj.2015.36

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] P-glycoprotein is expressed and causes resistance to chemotherapy in EBV-positive T-cell lymphoproliferative diseases2015

    • Author(s)
      Yoshimori M, Takada H, Imadome K, Kurata M, Yamamoto K, Koyama T, Shimizu N, Fujiwara S, Miura O and Arai A
    • Journal Title

      Cancer medicine

      Volume: 4 Issue: 10 Pages: 1494-1504

    • DOI

      10.1002/cam4.494

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Deubiquitinase Inhibitor WP1130 Blocks FLT3-ITD to Induce Apoptosis in Leukemic Cells2017

    • Author(s)
      Hiroki Akiyama, Yoshihiro Umezawa, Keigo Okada, Shinya Ishida, Ayako Nogami, and Osamu Miura
    • Organizer
      The 59th American Society of Hematology Annual Meeting & Exposition
    • Related Report
      2017 Annual Research Report
  • [Presentation] Modulation of the mTORC1 pathway by ubiquitin-proteasome system via REDD1 in AML with FLT3-ITD2017

    • Author(s)
      Ayako Nogami, Keigo Okada, Cheng Chen, Maho Kawakami, Hiroki Akiyama, Yoshihiro Umezawa, Gaku Oshikawa, Shinya Ishida, Tetsuya Kurosu, Osamu Miura
    • Organizer
      第 79 会日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Autophagy and Bcl-2 family members protect JAK2-V617F-expressing leukemic cells from ruxolitinib2017

    • Author(s)
      Shinya Ishida, Gaku Oshikawa, Toshikage Nagao, Keigo Okada, Hiroki Akiyama, Yoshihiro Umezawa, Ayako Nogami, and Osamu Miura
    • Organizer
      第 79 回日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] FLT3-ITD confers resistance to PI3K/Akt inhibitors by enhancing mTORC1/Mcl- 1 pathway via Pim kinase2017

    • Author(s)
      Keigo Okada, Ayako Nogami, Cheng Chen, Maho kawakami, Hiroki Akiyama, Shinya Ishida, Yoshihiro Umezawa, Osamu Miura
    • Organizer
      第 79 回日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Deubiquitinase inhibitor WP1130 blocks JAK2-V617F to induce apoptosis in leukemic cells2017

    • Author(s)
      Hiroki Akiyama, Yoshihiro Umezawa, Keigo Okada, Shinya Ishida, Ayako Nogami, Toshikage Nagao, Osamu Miura
    • Organizer
      第 79 回日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Pim キナーゼによる mTOR 経路促進を介した FLT3-ITD による Bortezomib 抵抗性獲得機構2016

    • Author(s)
      野上 彩子、岡田 啓五、押川 学、石田 信也、秋山 弘樹、梅澤 佳央、黒須 哲也、三浦 修
    • Organizer
      第 78 回日本血液 学会学術集会
    • Place of Presentation
      神奈川県横浜市
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] PECAM-1 による PI3K/Akt/mTORC1 経路を介した SDF-1 誘導性走化能の亢進機構2016

    • Author(s)
      梅澤 佳央、秋山 弘樹、岡田 啓吾、石田 信也、野上 彩子、押川 学、黒須 哲也、三浦 修
    • Organizer
      第 78 回日本血液学会学術集会
    • Place of Presentation
      神奈川県横浜市
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] Deubiquitinase inhibitor WP1130 blocks JAK2-V617F and FLT3-ITD to induce apoptosis in leukemic cells2016

    • Author(s)
      Hiroki Akiyama,Yoshihiro Umezawa,Keigo Okada,Shinya Ishida,Ayako Nogami,Gaku Oshikawa, Osamu Miura
    • Organizer
      第 78 回日本血液学会学術集会
    • Place of Presentation
      神奈川県横浜市
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] FLT3-ITD による STAT5、Pim-1 と mTOR 経路を介した Bortezomib 耐性誘導機構2015

    • Author(s)
      野上 彩子、岡田 啓五、押川 学、石田 信也、秋山 弘樹、梅澤 佳央、黒須 哲也、三浦 修
    • Organizer
      第 77 回日本血液学会学術集会
    • Place of Presentation
      石川県金沢市石川県立音楽堂
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report
  • [Presentation] Roles for BTK in JAK2-V617F-positive PVTL-1 cells resistant to the Jak kinase inhibitor ruxolitinib2015

    • Author(s)
      Ishida S, Oshikawa G, Nogao T, Okada K, Akiyama H, Umezawa Y, NOgami A, Miura O
    • Organizer
      第 77 回日本血液 学会学術集会
    • Place of Presentation
      石川県金沢市石川県立音楽堂
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report
  • [Presentation] Mechanisms of resistance to TKIs in novel JAK2-V617F-positive AML cell line, PVTL-2 and PVTL-12015

    • Author(s)
      Ishida S, Oshikawa G, Nogao T, Okada K, Akiyama H, Umezawa Y, Nogami A, Miura O .
    • Organizer
      第 77 回日本血液 学会学術集会
    • Place of Presentation
      石川県金沢市石川県立音楽堂
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report
  • [Presentation] FLT3-ITD confers resistance to PI3K/Akt inhibitors by inducing Pim kinases through STAT5 activation2015

    • Author(s)
      Keigo Okada, Ayako Nogami, Gaku Oshikawa, Shinya Ishida, Hiroki Akiyama, Yoshihiro Umezawa, Osamu Miura
    • Organizer
      第 77 回日本血液 学会学術集会
    • Place of Presentation
      石川県金沢市石川県立音楽堂金沢
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2019-03-29  

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