anti-leukemic activity of FLT3 inhibitor on childhood acute lymphoblastic leukemia with 11q23 translocation
| Project/Area Number |
16591018
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | University of Yamanashi |
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Principal Investigator |
SUGITA Kanji University of Yamanashi, Department of Research Interdisciplinary Graduate School of Medicine and Engineering, Associate professor, 大学院・医学工学総合研究部, 助教授 (60138055)
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| Co-Investigator(Kenkyū-buntansha) |
INUKAI Takeshi University of Yamanashi, Department of Research Interdisciplinary Graduate School of Medicine and Engineering, Research associate, 大学院・医学工学総合研究部, 助手 (30293450)
GOI Kumiko University of Yamanashi, Department of Research Interdisciplinary Graduate School of Medicine and Engineering, Research associate, 大学院・医学工学総合研究部, 助手 (70324192)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | PKC412 / anti-FLT3 agent / 11q23 translocation / childhood ALL / apoptosis / cell cycle arrest / 白血病細胞株 / STAT5 / Bim / 小児急性白血病 |
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| Research Abstract |
We examined the anti-leukemic activity of PKC412 (a kinase inhibitor of FLT3) against 11q23-translocated leukemia cell lines with or without D835 mutation and pursued the molecular mechanism(s) of its activity. B-precursor leukemic cell lines with 11q23 translocation expressed a higher FLT3 transcript on the real-time PCR analysis and showed a higher inhibition of ^3H-thymidine uptakes by PKC412 when compared with other B-precursor cell lines. This anti-leukemic activity of PKC412 was more profoundly revealed in 11q23-traslocated cell lines with D835 mutation, and was mainly mediated by the caspase-dependent induction of apoptosis. The PKC412-induced cell cycle arrest at the G0/G1 phase was also revealed in 11q23-translocated cell lines with or without D835 mutation. Regarding changes in signaling molecules after PKC412 treatment, constitutive phosphorylation of STAT5 and Akt was almost completely abolished and the proapoptotic BH3-only member Bim was strikingly upregulated, suggesting their causative roles in the PKC412-induced apoptosis. These results shed light on the molecular mechanism of the anti-leukemic activity of the FLT3 inhibitor(s) and provide a molecular basis to the prospect that PKC412 might become a potentially useful agent for the treatment of leukemia with 11q23 translocation, particularly having FLT3-TKD mutations.
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Report
(3 results)
Research Products
(32 results)
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[Journal Article] Induction of impaired membrane phospholipid asymmetry in mature erythrocytes after chemotherapy2005
Author(s)
Xiaochum Z, Inukai T, Hirose K, Akahane K, Nemoto A, Takahashi K, Sato H, Goi K, Kagami K, Sugita K, Nakazawa S.
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Journal Title
Int J Hematol 82
Pages: 132-136
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Journal Title
Blood 105
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[Journal Article] No advantage of dexamethasone over predonisolone for the outcome of standard and intermediate risk childhood acute lymphoblastic leukemia in the Tokyo Children's Cancer Study group L95-14 protocol.2005
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J Clin Oncol 20
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[Journal Article] Pivotal roles of Bim, a proapoptotic relative of Bcl-2, in the leukemogenesis of chronic myeloid leukemia.2004
Author(s)
Kuribara R, Honda H, Matsui H, Shinjyo T, Inukai T, Sugita K, Nakazawa S, Hirai H, Ozawa K, Inaba T.
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Journal Title
Mol Cell Biol 24
Pages: 6172-6183
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[Journal Article] Non-T-cell-depleted HLA haploidentical stem cell transplantation based on feto-maternal microchimerizm in pediatric patients with advanced malignancies.2004
Author(s)
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Journal Title
Bone Marrow Transpl 34
Pages: 373-375
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Harata M, Soda Y, Tani K, Ooi J, Takizawa T, Chen M, Bai Y, Izawa K, Kobayashi S, Tomonari A, Nagamura F, Takahashi S, Uchimaru K, Iseki T, Tsuji T, Takahashi TA, Sugita K, Nakazawa S, Tojo A, Maruyama K, Asano S.
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Author(s)
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Brit J Haematol 126
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Soda Y, Tani K, Bai Y, Saiki M, Chen M, Izawa K, Kobayashi S, Takahashi S, Uchiyama K, Kuwabara T, Warashina M, Tanabe T, Miyoshi H, Sugita K, Nakazawa S, Tojo A, Taira K, Asano S.
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