| Project/Area Number |
14570990
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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 |
OKUDA Tsukasa Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Department of Molecular-Targeting Cancer Prevention, Assistant Professor (Kohshi), 医学研究科, 講師 (30291587)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | AML1 / leukemia / RUNX / thymus / myelodysplastic syndrome / T-lymphocyte / hematopoiesis / knock-in mouse / RUNX1 / 転写因子 / 造血幹細胞 |
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| Research Abstract |
Acute Myeloid Leukemia 1 (AML1; also called as Runt-Related Transcription Factor 1: RUNX1) encodes a transcription factor which plays a pivotal role in early development of definitive hematopoiesis, and is the most frequent target of the leukemia-associated gene aberration. In this study, we examined its function along with normal and leukemic hematopoiesis by means of hematopoietic rescue assay at embryonic stem cell and entire mouse levels. What we found are summarized as follows:
1.Transcription-repressive function of AML1,which is mediated through its C-terminal VWRPY-motif, is not essential for the early hematopoietic development in the context of the entire mouse.
2.Genome-modified mouse lines which homozygously harbor knocked-in AML1 allele lacking of VWRPY-motif revealed that the genetically conserved VWRPY-motif plays an important role in early development of thymus and CD4-expression.
3.By screening 170 cases of leukemia or related disorders, we found five (2.9%) novel mutations within the exons 3 through 6,which correspond to the runt domain. Apart from a case with a silent mutation, the remaining four cases were all loss-of-function type of the allele : Two of them were frame-shift near the N-terminus, and the other two, I150ins and K168,were insertion mutations near the C-terminal end of the runt domain which were experimentally proven to be non-functional. These data further underscore the notice that one-allele loss of AML1 serves as an early event of human leukemogenesis.
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