Combined Anti-Leukemia Therapy Targeting Constitutively Activated Tyrosine Kinases and Checkpoint Activation Mechanisms

• Project/Area Number: 21591194
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• 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, 大学院・医歯学総合研究科, 教授 (10209710)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2009: ¥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 / BCR/ABL / imatinib / Flt3-ITD / sorafenib / Jak2-V617F / etoposide / Chkl / HSP90 / p53 / nutlin-3 / Mdm2阻害薬 / chk1 / BCR / ABL

Research Abstract

Constitutively activated aberrant tyrosine kinases play important roles in development and evolution of hematopoietic malignancies and are also implicated in acquisition of therapy resistance. We found that the chemotherapy resistance of hematopoietic cells transformed by BCR/ABL, Flt3-ITD, or Jak2-V617F could be conquered by combining specific tyrosine kinase inhibitors against these aberrant kinases with DNA-damaging chemotherapeutic agents and elucidated the underlying molecular mechanisms.

Research Products

• [Journal Article] c-Cbl and Cbl-b ligases mediate 17-allylaminodemethoxygeldanamycin-in duced degradation of autophosphorylated Flt3 kinase with internal tandem duplication through the ubiquitin proteasome pathway (2011)
  • Author(s): Oshikawa G, Nagao T, Wu N, Kurosu T, Miura O
  • Journal Title: J Biol Chem Volume: 286 Pages: 30263-30273
  • Peer Reviewed
• [Journal Article] DNA damage stress and inhibition of Jak2-V617F cause its degradation and synergistically induce apoptosis through activation of GSK3beta (2011)
  • Author(s): Nagao T, Oshikawa G, Wu N, Kurosu T, Miura O
  • Journal Title: PLoS ONE Volume: 6
  • Peer Reviewed
• [Journal Article] Novel mouse xenograft models reveal a critical role of CD4+T cells in the proliferation of EBV-infected T and NK cells (2011)
  • Author(s): Imadome K, Yajima M, Arai A, Nakazawa A, Kawano F, Ichikawa S, Shimizu N, Yamamoto N, Morio T, OhgaS, Nakamura H, Ito M, Miura O, KomanoJ, Fujiwara S
  • Journal Title: PLoS Pathog Volume: 7
  • Peer Reviewed
• [Journal Article] Clinical features of adult-onset chronic active Epstein-Barr virus infection : a retrospective analysis (2011)
  • Author(s): Arai A, Imadome K, Watanabe Y, Yoshimori M, Koyama T, Kawaguchi T, Nakaseko C, Fujiwara S, Miura O
  • Journal Title: Int J Hematol Volume: 93 Pages: 602-609
  • NAID: 10029535036
  • Peer Reviewed
• [Journal Article] c-Cb1 and Cb1-b ligases mediate 17-allylaminodeniethoxygeldanamycin-induced degradation of autophosphorylated Flt3 kinase with internal tandem duplication through the ubiquitin proteasome pathway (2011)
  • Author(s): Oshikawa G, Nagao T, Wu N, Kurosu T, Miura O
  • Journal Title: J Biol Chem Volume: 286 Pages: 30263-30273
  • Peer Reviewed
• [Journal Article] Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway (2010)
  • Author(s): Kurosu T, Wu N, Oshikawa G, Kagechika H, Miura O
  • Journal Title: Apoptosis Volume: 15 Pages: 608-620
  • Peer Reviewed
• [Journal Article] Clonal evolution with double Ph followed by tetraploidy in imatinib-treated chronic myeloid leukemia with e19a2 transcript in transformation (2010)
  • Author(s): Oshikawa G, Kurosu T, Arai A, Murakami N, Miura O
  • Journal Title: Cancer Genet Cytogenet Volume: 199 Pages: 56-61
  • Peer Reviewed
• [Journal Article] Concurrent administration of intravenous systemic and intravitreal methotrexate for intraocular lymphoma with central nervous system involvement (2010)
  • Author(s): Nakauchi Y, Takase H, Sugita S, Mochizuki M, Shibata S, Ishiwata Y, Shibuya Y, Yasuhara M, Miura O, AraiNakauchi Y, Takase H, Sugita S, Mochizuki M, Shibata S, Ishiwata Y, Shibuya Y, Yasuhara M, Miura O, Arai A
  • Journal Title: Int J Hematol Volume: 92 Pages: 179-185
  • NAID: 10026512401
  • Peer Reviewed
• [Journal Article] Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway. (2010)
  • Author(s): Kurosu T, Wu N, Oshikawa G, Kagechika H, Miura O.
  • Journal Title: Apoptosis Volume: 15 Pages: 608-620
  • Peer Reviewed
• [Journal Article] Clonal evolution with double Ph followed by tetraploidy in imatinib-treated chronic myeloid leukemia with e19a2 transcript in transformation. (2010)
  • Author(s): Oshikawa G, Kurosu T, AraiA, Murakami N, Miura O.
  • Journal Title: Cancer Genet Cytogenet Volume: 199 Pages: 56-61
  • Peer Reviewed
• [Journal Article] Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway (2009)
  • Author(s): Kurosu T, Ohki M, Wu N, Kagechika H, Miura O
  • Journal Title: Cancer Res Volume: 69 Pages: 3927-3936
  • Peer Reviewed
• [Journal Article] Extranodal NK/T cell lymphoma, nasal type, of the small intestine diagnosed by double-balloon endoscopy (2009)
  • Author(s): Wakabayashi S, Arai A, Oshikawa G, Araki A, Watanabe M, Uchida N, Taniguchi S, Miura O
  • Journal Title: Int J Hematol Volume: 90 Pages: 605-610
  • NAID: 10026110013
  • Peer Reviewed
• [Journal Article] Role for protein geranylgeranylation in adult T-cell leukemia cell survival (2009)
  • Author(s): Nonaka M, Uota S, Saitoh Y, Takahashi M, Sugimoto H, Amet T, Arai A, Miura O, Yamamoto N, Yamaoka S
  • Journal Title: Exp Cell Res Volume: 315 Pages: 141-150
  • Peer Reviewed
• [Journal Article] Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway. (2009)
  • Author(s): Kurosu T, Ohki M, Wu N, Kagechika H, Miura O.
  • Journal Title: Cancer Res 69 Pages: 3927-36
  • Peer Reviewed
• [Presentation] c-Cbl and Cbl-b mediate 17-AAG-induced Flt3-ITD degradation through the ubiquitin proteasome pathway (2011)
  • Author(s): Oshikawa G, Nagao T, Wu N, Kurosu T, Miura O.
  • Organizer: 第73回日本血液学会総
  • Place of Presentation: 名古屋
• [Presentation] PECAM-1 possibly mediates BCR/ABL signaling and modulates imatinib sensitivity of Ph+leukemic cells (2011)
  • Author(s): Wu N, Kurosu T, Oshikawa G, Nagao T, Miura O.
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
• [Presentation] Inhibition of BCR/ABL downregulates Chk1 to induce apoptosis synergistically with chemotherapeutics (2011)
  • Author(s): Kurosu T, Wu N, Oshikawa G, Nagao T, Miura O.
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
• [Presentation] Inhibition of Jak2-V617F under DNA-damage stress induces its degradation and synergistic apoptosis (2011)
  • Author(s): Nagao T, Oshikawa G, Wu N, Kurosu T, Miura O.
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
• [Presentation] c-Cbl-mediated ubiquitination of Flt3-ITD and cellular mechanisms regulating its degradation (2010)
  • Author(s): Oshikawa G, Wu N, Nagao T, Suzki T, Kurosu T, Miura O.
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] Roles for PECAM-1(CD31) in signaling from and leukemogenesis by BCR/ABL (2010)
  • Author(s): Wu N, Kurosu T, Suzuki T, Oshikawa G, Nagao T, Miura O.
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] Molecular mechanisms regulating DNA damage-induced degradation of Jak2-V617F and apoptosis (2010)
  • Author(s): Nagao T, Wu N, Oshikawa G, Suzuki T, Kurosu T, Miura O.
  • Organizer: 第72回日本血液学会総
  • Place of Presentation: 横浜
• [Presentation] Chemotherapy resistance through enhanced Chk1 activation by BCR/ABL, Flt-ITD and Jak2-V617F (2010)
  • Author(s): Kurosu T, Wu N, Suzuki T, Oshikawa G, Nagao T, Miura O.
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] Chemotherapy resistance through enhanced Chkl activation by BCR/ABL, Flt3-ITD and Jak2-V617F (2010)
  • Author(s): 黒須哲也, 呉楠 , 鈴木隆之, 拝長尾俊景, 三浦修
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] c-Cbl-mediated ubiquitination of Flt3-ITD and cellular mechanismsregulating its degradation (2010)
  • Author(s): 押川学, 呉楠., 長尾俊景, 黒須哲也, 三浦 修
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] Molecular mechanisms regulating DNA damage-induced degradation of Jak2-V617F and apoptosis (2010)
  • Author(s): 長尾俊景, 呉楠, 押川学, 鈴木隆之, 黒須哲也, 三浦修
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] Roles for PECAM-1(CD31)in signaling from and leukemogenesis by BCR/ABL (2010)
  • Author(s): 呉楠, 黒須哲也, 鈴木隆之, 押川学, 長尾俊景, 三浦修
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] BCR/ABL発現細胞におけるimatinib誘導性アポトーシスのnutlin-3aによるp53活性化を介した相乗的亢進機構 (2009)
  • Author(s): 黒須哲也、呉楠、大木学、押川学、長尾俊景、鈴木隆之、三浦修
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/hema/details/research.htm