Development of combined molecular target therapy against hematopoietic malignancies expressing constitutively activated tyrosine kinases

• Project/Area Number: 24591384
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MIURA Osamu 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (10209710)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 急性骨髄性白血病 / 骨髄増殖性腫瘍 / チロシンキナーゼ阻害薬 / 分子標的療法 / FLT3 / Jak2 / STAT5 / PECAM-1 / 造血器腫瘍 / チロシンキナーゼ

Outline of Final Research Achievements

The molecular mechanisms for resistance of acute myeloid leukemia and myeloproliferative neoplasms, such as chronic myeloid leukemia, against chemotherapy and molecular target therapy conferred by constitutively activated tyrosine kinases, such as FLT3-ITD, BCR/ABL and Jak2-V617 were analyzed. These aberrant tyrosine kinases were found to enhance Chk1-mediated cell cycle checkpoint mechanisms induced by chemotherapeutics to confer resistance to chemotherapy or protect the downstream mTOR pathway from inhibition of the PI3K/Akt pathway by robustly activating STAT5 to confer resistance to the PI3K/Akt inhibitors. Combined therapeutic strategies to control these resistance mechanisms have shown to induce apoptosis of leukemic cells synergistically and very effectively.

Research Products

• [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 leukemia. (2015)
  • Author(s): Nogami A, Oshikawa G, Okada K, Fukutake S, Umezawa Y, Nagao T, Kurosu T, Miura O
  • Journal Title: Oncotarget Volume: 6 Pages: 9189-9205
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel MYD88 mutation, L265RPP, in Waldenström macroglobulinemia activates the NF-κB pathway to up regulate Bcl-xL expression and enhances cell survival (2015)
  • Author(s): Toshikage Nagao, Gaku Oshikawa, Shinya Ishida, Hiroki Akiyama, Yoshihiro Umezawa, Ayako Nogami, Tetsuya Kurosu, and Osamu Miura
  • Journal Title: Blood Cancer Journal Volume: 5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proliferation and survival signaling from both Jak2-V617F and Lyn involving GSK3 and mTOR/p70S6K/4EBP1 in PVTL-1 cell line newly established from acute myeloid leukemia transformed from polycythemia vera. (2014)
  • Author(s): Nagao T, Kurosu T, Umezawa Y, Nogami A, Oshikawa G, Tohda S, Yamamoto M, Miura O
  • Journal Title: PLoS One Volume: 9 Issue: 1 Pages: e84746-e84746
  • DOI: 10.1371/journal.pone.0084746
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of the PI3K/Akt/GSK3 Pathway Downstream of BCR/ABL, Jak2-V617F, or FLT3-ITD Downregulates DNA Damage-Induced Chk1 Activation as Well as G2/M Arrest and Prominently Enhances Induction of Apoptosis (2013)
  • Author(s): Kurosu T, Nagao T, Wu N, Oshikawa G, Miura O
  • Journal Title: PLoS One Volume: 8 Issue: 11 Pages: e79478-e79478
  • DOI: 10.1371/journal.pone.0079478
  • Peer Reviewed
• [Journal Article] CD137 Is Induced by the CD40Signal on Chronic Lymphocytic Leukemia B Cells and Transduces the Survival Signal via NF-κB Activation (2013)
  • Author(s): Nakaima Y, Watanabe K, Koyama T, Miura O, Fukuda T
  • Journal Title: PLoS One Volume: 8(5) Issue: 5 Pages: e64425-e64425
  • DOI: 10.1371/journal.pone.0064425
  • Peer Reviewed
• [Journal Article] PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced apoptosis of Philadelphia chromosome-positiveleukemia cells (2013)
  • Author(s): Wu N, Kurosu T, Oshikawa G, Nagao T,Miura O
  • Journal Title: Int J Oncol Volume: 42(2) Issue: 2 Pages: 419-28
  • DOI: 10.3892/ijo.2012.1729
  • Peer Reviewed
• [Presentation] Flt3-ITD confers resistance to PI3K/Akt inhibitors by protecting mTOR/eIF4F/Mcl-1 pathway via STAT5 (2014)
  • Author(s): Ayako Nogami, Gaku Oshikawa, Shinya Ishida, Hiroki Akiyama, Yoshihiro Umezawa, Toshikage Nagao, Tetsuya Kurosu, Osamu Miura
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31
• [Presentation] PECAM-1 enhances SDF-1-induced chemotaxis mediated through activation of the PI3K/Akt/mTORC1 pathway (2014)
  • Author(s): Yoshihiro Umezawa, Hiroki Akiyama, Shinya Ishida, Ayako Nogami, Gaku Oshikawa, Toshikage Nagao, Tetsuya Kurosu, Osamu Miura
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31
• [Presentation] Molecular basis for differential responses of FlT3-ITD and TKD to P13K/Akt and proteasome inhibitors. (2013)
  • Author(s): Nogami A, Oshikawa G, Fukutake S, Nagao T, Umezawa Y, Kurosu T, Miura O.
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 札幌
• [Presentation] Molecular biological analysis of a novel MYD88 mutation, L265-RPP, in Waldenstrom macroglobulinemia (2013)
  • Author(s): Nagao T, Umezawa Y, Nogami A, Kurosu T, Miura O.
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 札幌
• [Presentation] Roles of tyrosine kinases in B-cell receptor signaling regulating survival of CLL B cells (2013)
  • Author(s): Kato M, Watanabe K, Suwa S, Iida M, Tohda S, Miura O, Fukuda T.
  • Organizer: 第75回日本血液学会総会
  • Place of Presentation: 札幌
• [Presentation] BCR/ABL発現細胞におけるChk1とp53を介した細胞周期チェックポイント活性化の相互調節機構 (2012)
  • Author(s): 黒須 哲也、呉 楠、野上 彩子、押川 学、長尾 俊景、三浦 修
  • Organizer: 第７４回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Flt3-ITD及びFlt3-TKD発現細胞の分子標的薬への感受性の差違とその分子基盤 (2012)
  • Author(s): 押川 学、長尾 俊景、野上 彩子、呉 楠、黒須 哲也、三浦 修
  • Organizer: 第７４回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Simvastatin Induces Apoptosis in EBV-Positive T- or NK-Cell Lymphoproliferative Disorders and Anti-Tumor Effects in Xenograft Models.
  • Author(s): Arai A, Horino M, Wang L, Imadome K, Hamasaki K, Kurata M, Ichikawa A, Fujiwara S, Miura O.
  • Organizer: The 4th JSH International Symposium
  • Place of Presentation: 松山