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

• Project/Area Number: 18K08349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tokyo 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, 教授 (10209710)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 血液腫瘍学 / 分子標的療法 / チロシンキナーゼ / FLT3-ITD / JAK2-V617F / プロテアソーム阻害薬 / USP9X / RSK / 造血器腫瘍 / 急性骨髄性白血病 / 骨髄増殖性腫瘍 / BCR/ABL / シグナル伝達

Outline of Final Research Achievements

We have aimed to gain new insights to develop novel molecular targeted therapies against hematopoietic malignancies with constitutively activated aberrant tyrosine kinase mutants, which play important roles not only in pathogenesis but also in acquisition of therapy resistance. We have elucidated the molecular mechanisms underlying resistance of FLT3-ITD acute myeloid leukemia to proteasome inhibitors and also have found that USP9X and RSK1 represent particularly effective targets for therapies against this disease with poor prognosis especially when the STAT5/Pim/mTORC1/Mcl-1 pathway is targeted in combination. Furthermore, USP9X was found to be a promising therapeutic target also for JAK2-V617F-positive myeloproliferative neoplasms, with its inhibitor as well as BH3 mimetics showing prominent effects particularly in ruxolitinib persistent cells.

Academic Significance and Societal Importance of the Research Achievements

本研究は種々の造血器腫瘍で高頻度に認められる代表的かつ重要な恒常的活性化型チロシンキナーゼ変異体に関して、それぞれの疾患の発症や進展のみでなく治療抵抗性獲得にも寄与する細胞内シグナル伝達機構を新たな因子や伝達経路の関与を含めて詳細に明らかにするもので、細胞生物学や腫瘍治療学研究の発展に寄与する学術的意義を有するものである。また、臨床開発中や臨床応用がなされている分子標的薬等を用いた検討により得られた成果は、難治性造血器腫瘍の新規統合的分子標的療法開発へ向けて臨床的にも直接的に貢献しうる社会的意義を有する。

Research Products

• [Journal Article] Inhibition of USP9X Downregulates JAK2-V617F and Induces Apoptosis Synergistically with BH3 Mimetics Preferentially in Ruxolitinib-Persistent JAK2-V617F-Positive Leukemic Cells (2020)
  • Author(s): Akiyama Hiroki、Umezawa Yoshihiro、Watanabe Daisuke、Okada Keigo、Ishida Shinya、Nogami Ayako、Miura Osamu
  • Journal Title: Cancers Volume: 12 Issue: 2 Pages: 406-406
  • DOI: 10.3390/cancers12020406
  • Peer Reviewed / Open Access
• [Journal Article] FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM (2019)
  • Author(s): Watanabe、Nogami、Okada、Akiyama、Umezawa、Miura
  • Journal Title: Cancers Volume: 11 Issue: 12 Pages: 1827-1827
  • DOI: 10.3390/cancers11121827
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of the STAT5/Pim Kinase Axis Enhances Cytotoxic Effects of Proteasome Inhibitors on FLT3-ITD-Positive AML Cells by Cooperatively Inhibiting the mTORC1/4EBP1/S6K/Mcl-1 Pathway (2019)
  • Author(s): A. Nogami, K. Okada, S. Ishida, H. Akiyama, Y. Umezawa, O. Miura
  • Journal Title: Translational oncology Volume: 12 Issue: 2 Pages: 336-349
  • DOI: 10.1016/j.tranon.2018.11.001
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of USP9X induces apoptosis in FLT3-ITD-positive AML cells cooperatively by inhibiting the mutant kinase through aggresomal translocation and inducing oxidative stress (2019)
  • Author(s): H. Akiyama, Y. Umezawa, S. Ishida, K. Okada, A. Nogami, O. Miura
  • Journal Title: Cancer letters Volume: 453 Pages: 84-94
  • DOI: 10.1016/j.canlet.2019.03.046
  • Peer Reviewed
• [Presentation] FLT3-ITD activates RSK1 to upregulate mTORC1 and eIF4B and to inhibit BAD and BIM (2020)
  • Author(s): Daisuke Watanabe, Ayako Nogami, Keigo Okada, Hiroki Akiyama, Yoshihiro Umezawa, Toshikage Nagao, Osamu Miura
  • Organizer: 第 82 回日本血液学会学術集会
• [Presentation] Overexpression of MPL causes ruxolitinib-resistance in MPN with CALR frame-shift mutations (2020)
  • Author(s): Shunichiro Yasuda, Satoru Aoyama, Ryoto Yoshimoto, Daisuke Watanabe, Kouhei Yamamoto, Takeo Fujiwara,Yoko Edahiro, Misa Imai, Marito Araki, Norio Komatsu, Osamu Miura, Norihiko Kawamata
  • Organizer: 第 82 回日本血液学会学術集会
• [Presentation] FLT3-ITD Enhances Proliferation and Survival of AML Cells through Activation of RSK1 to Upregulate the mTORC1/eIF4F Pathway Cooperatively with PIM or PI3K and to Inhibit Bad and Bim. (2019)
  • Author(s): Ayako Nogami, Daisuke Watanabe, Keigo Okada, Hiroki Akiyama, Yoshihiro Umezawa, Toshikage Nagao, Shuji Tohda, Osamu Miura
  • Organizer: 2019 American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Deubiquitinase Inhibitor WP1130 Exerts Anti-leukemic Effect by Causing Aggresomal Translocation of FLT3-ITD and Oxidative Stress to Induce Apoptosis (2019)
  • Author(s): Hiroki Akiyama, Yoshihiro Umezawa, Keigo Okada, Daisuke Watanabe, Shinya Ishida, Ayako Nogami, Osamu Miura
  • Organizer: The 9th JSH International Symposium 2018
  • Int'l Joint Research
• [Presentation] Proteasome Inhibitors Downregulate the mTORC1/4EBP1/S6K/Mcl-1 Pathway Cooperatively with Inhibitors for The STAT5/Pim Kinase Pathway to Induce Apoptosis in FLT3-ITD-positive AML Cells (2018)
  • Author(s): Ayako Nogami, Keigo Okada, Daisuke Watanabe, Hiroki Akiyama, Yoshihiro Umezawa, Shinya Ishida, Gaku Oshikawa, Shuji Tohda, Osamu Miura
  • Organizer: The 9th JSH International Symposium 2018
  • Int'l Joint Research