2005 Fiscal Year Final Research Report Summary
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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| Keywords | PKC412 / anti-FLT3 agent / 11q23 translocation / childhood ALL / apoptosis / cell cycle arrest |
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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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Research Products
(30 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
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] TEF, an anti-apoptotic bZIP transcription factor related to the oncogenic E2A-HLF chimera, inhibits cell growth by downregulating expression of the common b chain of cytokine receptors.2005
Author(s)
Inukai T, Inaba T, Dang J, Kuribara R, Ozawa K, Miyajima A, Wu Wenshu, Look AT, Arinobu Y, Iwasaki H, Akashi K, Kagami K, Goi K, Sugita K, Nakazawa S.
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Journal Title
Blood 105
Pages: 4437-4444
Description
「研究成果報告書概要(欧文)」より
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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
Author(s)
Igarashi S, Manabe A, Ohara A, Kumagai M, Saito T, Okimoto Y, Kamijo T, Isoyama K, Kajiwara M, Sotomatsu M, Sugita K, Sugita K, Maeda M, Yabe H, Kinoshita T, Kaneko T, Hayashi Y, Ikuta K, Hanada R, Tsuchiya M.
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Journal Title
J Clin Oncol 20
Pages: 6489-6498
Description
「研究成果報告書概要(欧文)」より
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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
Description
「研究成果報告書概要(欧文)」より
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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)
Yoshihara T, Morimoto A, Inukai T, Kuroda H, Ishida H, Sugita K, Goi K, Imamura T, Todo S, Maruya E, Saji H, Nakazawa S, Imashuku S.
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Journal Title
Bone Marrow Transpl 34
Pages: 373-375
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells.2004
Author(s)
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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Journal Title
Blood 104
Pages: 1442-1449
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of protein Sα gene mutations including four novel mutations in eight unrelated patients with protein S deficiency.2004
Author(s)
Okada H, Takagi A, Murate T, Adach T, Yamamoto K, Matsushita T, Takamatsu J, Sugita K, Sugimoto M, Yoshioka A, Yamazaki T, Saito H, Kojima T.
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Journal Title
Brit J Haematol 126
Pages: 219-225
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A novel Maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive acute lymphoblastic leukemia2004
Author(s)
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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Journal Title
Description
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