| Project/Area Number |
22390197
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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 | National Cancer Center Japan |
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Principal Investigator |
KITABAYASHI Issay 独立行政法人国立がん研究センター, 研究所, 分野長 (20261175)
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| Co-Investigator(Renkei-kenkyūsha) |
YOKOYAMA Akihiko 京都大学, メディカルイノベーションセンター, 特定准教授 (10506710)
YAMAGATA Kazutsune 独立行政法人国立がん研究センター, 研究所, 研究員 (70311412)
KATSUMOTO Takuo 独立行政法人国立がん研究センター, 研究所, 研究員 (50469970)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2012: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2011: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2010: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
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| Keywords | 血液腫瘍学 / acute myeloid leukemia / nucleophosmin / YB-1 / 白血病 / 幹細胞 / NPM / NPMc |
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| Research Abstract |
Nucleophosmin (NPM) is frequently mutated in acute myeloid leukemia (AML), which results in changes of its localization from nucleolus to cytoplasm. The cytoplasmic NPM (NPMc) is thought to be important for leukemogenesis, but the molecular mechanism by which NPMc exerts its leukemogenic potential has never been established. Here we show that ectopic expression of NPMc, but not wild type (WT) NPM, in mouse bone marrow progenitor cells enhanced their colony formation activity, which is associated with increased expression of HoxA9 gene. These data suggest that up-regulation of HoxA9 gene is involved in NPMc-mediated leukemogenesis. By using a set of NPMc mutant, we found that nuclear export signal and oligomerization domain is required for NPMc-mediated transformation activity. This result suggests that NPMc act as an oncogene by sequestering wild type NPM from nucleolus into cytoplasm.To clarify the roles of NPMc in leukemogenesis, we purified the NPM complex and identified YB-1 as a binding partner for NPM. The colony formation activity and expression of Hoxa9 gene, which were increased by NPMc, were impaired in YB-1 null cells. YB-1 was associated with a protein complex, which regulates mRNA stability including Hoxa9 mRNA. These results suggest that YB-1 is required for NPMc-mediated transformation of hematopoietic1 progenitor cells possibly through stabilization of Hoxa9 mRNA.
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