Leukemogenic Mechanism by genomic mutations of hematopoietic-speci is transcription factor, AML1/RUNX1
| Project/Area Number |
18591078
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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, Professor (30291587)
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| Co-Investigator(Kenkyū-buntansha) |
HORIIKE Shigeo Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Lecturer (10209273)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | cancer / leukemia / genome-modified mouse / transcription factor / RUNX1 / AML1 / retrovirus |
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| Research Abstract |
Hematopoietic transcription factor AML1 (RUNX1) is a frequent target of leukemia-associated chromosome translocations. AML1 is rearranged by chromosome translocations to form chimera protein which acts as a strong trans-dominant inhibitor against wild-type AML1 and contributes to leukemia development, while mis-sense mutations at DNA-contacting residues of the molecule have also been recognized as leukemia-associated mutations recently. In this study we assessed the consequences of these point mutations in context of entire animal. We successfully introduced each of the mutations, R139Q, R174Q, R177Q, or I150ins, into mouse germline through the knock-in approach. All mouse lines were embryonic lethal when inherited homozygously, indicating that these alleles are all loss-of-function type mutations. In contrast, heterozygotes for each mutation were normally born and developed healthy. They were fertile and developed no overt leukemia through their lives. Thus, these mutations seem to be insufficient to cause clinical leukemia as single allele, showing sharp contrast to the case for human diseases. Thus, it was suggested that additional co-operative mutation (s) are required to develop the disease. In order to address this issue, we performed retroviral-infection experiment using R174Q mice, and found that heterozygotes had tendency to develop leukemia earlier than their wild-type littermates did. This observation indicates that one allele mutation of AML1 serves to promote leukemia-onset one step further. In addition, cloning-analysis for proviral integration sites within the leukemia genome revealed a number of candidate co-operative genes. We are currently analyzing these gene products to see if they collaborate in human diseases.
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Report
(3 results)
Research Products
(12 results)
