2006 Fiscal Year Final Research Report Summary
Analysis of aberrant signal tansduction in hematological malignancy and development of treatment methods.
| Project/Area Number |
16390276
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Nagoya University |
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Principal Investigator |
NAOE Tomoki Nagoya University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (50217634)
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| Co-Investigator(Kenkyū-buntansha) |
ABE Akihiro Nagoya University, Graduate School of Medicine, Designated Assistant Professor, 大学院医学系研究科, 特任講師 (00432261)
KIYOI Hitoshi University Hospital, Assistant Professor, 医学部附属病院, 講師 (90314004)
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| Project Period (FY) |
2004 – 2006
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| Keywords | leukemia / cell signaling / JAK2 / JAK3 / target therapy / surrogate marker |
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| Research Abstract |
In this study, we aimed to explore new target molecules and develop signal inhibitors which are specifically effective to hematological malignancies. This year we searched mutation focusing on JAK2 and JAK3. JAK2 V617F mutation was found in 7 of 7 acute leukemia patients who were transformed from MPD. Neither p53, N-RAS and FLT3 mutations were identified in these patients but additional chromosomal rearrangements were found, suggesting addition of chromosomal abnormalities to the JAK2 mutation were associated with the transformation. JAK3 mutations were found in 2 of AML (M7) patients at the position of pseudokinase and receptor binding domains. Accordingly JAK2 and JAK3 which are dominantly mutated in leukemia are new target molecules. In FLT3-signaling, STAT5 is phosphorylated in a mutant-dependent manner. We investigated why STAT5 is specifically phosphorylated in mutant FLT3 signaling. Mutant FLT3 recruited a Src-family kinase Lyn which phosphorylated STAT5 in vivo and in vitro. The level of STAT5 phosphorylation was correlated with the activity of FLT3 kinase-inhibitors. These data suggest that phosphor-STAT5 is a new surrogate marker in FLT3-targeted therapy.
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