1999 Fiscal Year Final Research Report Summary
| Project/Area Number |
10670960
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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 |
Hematology
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
YOKOTA Shohei Kyoto Pref.Univ.Med., Dept.Medicine, 医学部, 助手 (80231687)
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| Co-Investigator(Kenkyū-buntansha) |
OKUDA Tsukasa Kyoto Pref.Univ.Med., Dept.Hygiene, Instructor, 医学部, 講師 (30291587)
SONODA Yoshiaki Kyoto Pref.Univ.Med., Dept.Hygiene, Professor, 医学部, 助教授 (60206688)
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| Project Period (FY) |
1998 – 1999
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| Keywords | FLT3 gene / tyrosine kinase / mutation / acute myelogenous leukemia / tandem duplication / myelodysplastic syndrome |
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| Research Abstract |
FLT3 (FMS-like tyrosine kinase 3) is a member of type 3 receptor tyrosine kinase. The structure is similar to the family gene, KIT, FMS, and PDGR. We have found internal tandem duplication (TD) in the juxta membrane domain of this gene in approximately 20% of adult AML cases and 5% of childhood AML cases. In this research project, we have clarified the prognostic significance of the FLT3/TD in AML patients and the some biological function of this gene alteration which may act for worsening the prognosis of leukemia. In adult cases of AML, FLT/TD has been elucidated as the most valuable factor for predicting the prognosis. In childhood AML cases, those with this mutation had also significantly shorter disease-free survival than those with wild-type.
To elucidate the biological relevance of the FLT3/TD, we preformed expression studies by inserting various types of mutant FLT3 into the Cos 7 cells. These studies have shown that all mutant FLT3 molecules were ligand-independently dimerized with their tyrosine residues phosphorylated. This constitutional dimerization does not depend on either sight of TD in the juxta membrane domain or the length of inserted nucleotides. We suspect that FLT3/TD occurs through a DNA-replication error which might be caused by hairpin-like structure due to the palindromic DNA sequence between codon 593 and 602.
In vitro culture of leukemic cells (L-CFU assay) supported by a panel of cytokines including FLT3 ligand (FL) was also performed. The assays showed that the AML cells without FLT3/TD formed less colonies than those with FLT3/TD in the culture condition lacking FL. However, the addition of FL to the cultures affected less in FLT3/TD positive AML cells than the negative cells. These findings might meet the ligand-independent activation of FLT3 receptor by the mutation.
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[Publications] Yokota S, Nakao M, Horiike S, Seriu T, Iwai T, Kaneko H, Azuma H, Oka T, Takeda T, Watanabe A, Kikuta A, Asami K, Sekine I, Matsushita T, Tsuhciya T, Mimaya J, Koizumi S, Miyake M, Nishikawa K, Takaue Y, Kawano Y, Iwai A, Ishida Y, Matsumoto K, Kawakami K, Hyakuna N, Tsurusawa M, Fujimoto T.: "Mutational analysis of the N-ras gene in acute lymphoblastic leukemia : a study of 125 Japanese pediatric cases"Internatl J Hematol. 67(4). 379-388 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Iwai T, Yokota S, Nakao M, Nakazawa N, Taniwaki M, Kimura T, Sonoda Y, Kaneko H, Okuda T, Azuma H, Oka T, Takeda T, Watanabe A, Kikuta A, Asami K, Sekine I, Matsushita T, Tsuchiya T, Mimaya J, Koizumi S, Ohta S, Miyake M, Takaue Y, Iwai A, Fujimoto T.: "Frequent aberration of FHITgene expression in acute leukemias"Cancer Res. 58(22). 5182-5187 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R.: "Prognostic Implication of FLT3 and N-RAS Gene Mutations in Acute Myeloid Leukemia"Blood. 93. 3074-3080 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Iwai T, Yokota S, Nakao M, Okamoto T, Taniwaki M, Onodera N, Watanabe A, Kikuta A, Tanaka A, Asami K, Sekine I, Mugishima H, Nishimura Y, Koizumi S, Horikoshi Y, Mimaya J, Ohta S, Nishikawa K, Iwai A, Shimokawa T, Nakayama M, Kawakami K, Gushiken T, Hyakuna N, Fujimoto T.: "Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan"Leukemia. 13(1). 38-43 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Kimura T, Sakabe H, Minamiguchi H, Fujiki H, Abe T, Kanebo H, Yokota S, Nakagawa H, Fujii H, Tamaki H, Ogawa H, Sugiyama H, Sonoda Y.: "Interleukin-11(IL-11) enhances clonal proliferation of acute myelogenous leukemia cells with strong expression of the IL-11 receptor alpha chain and signal transducing gp130"Leukemia. 13(7). 1018-1027 (1999)
Description
「研究成果報告書概要(欧文)」より
