2012 Fiscal Year Final Research Report
Development of the novel AML treatments by targeting leukemia stem cells
| 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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| Keywords | 血液腫瘍学 |
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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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[Journal Article] PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies.2013
Author(s)
Iwanami A, Gini B, Zanca C, Matsutani T, Assuncao A, Nael A, Dang J, Yang H, Zhu S, Kohyama J, Kitabayashi I, Cavenee WK, Cloughesy TF, Furnari FB, Nakamura M, Toyama Y, Okano H, Mischel PS
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Journal Title
Proc Natl Acad Sci USA
Volume: 110
Pages: 4339-4344
Peer Reviewed
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[Journal Article] Cancer susceptibility polymorphism of p53 at codon 72 affects phosphorylation and degradation of p53 protein.2011
Author(s)
Ozeki C, Sawai Y, Shibata T, Kohno T, Okamoto K, Yokota J, Tashiro F, Tanuma SI, Sakai R, Kawase T, Kitabayashi I, Taya Y, Ohki R
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Journal Title
J Biol Chem.
Volume: 286
Pages: 18251-18260
Peer Reviewed
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[Journal Article] The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis.2011
Author(s)
Mishima Y, Miyagi S, Saraya A, Negishi M, Endoh M, Endo TA, Toyoda T, Shinga J, Katsumoto T, Chiba T, Yamaguchi N, Kitabayashi I, Koseki H, Iwama A
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Journal Title
Blood
Volume: 118
Pages: 2443-53
Peer Reviewed
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[Journal Article] PU.1-mediated upregulation of M-CSFR is critical for leukemia stem cell potential induced by MOZ-TIF2.2010
Author(s)
Aikawa Y, Katsumoto K, Zhang P, Shima H, Shino M, Terui K, Ito E, Ohno H, Stanley ER, Singh H, Tenen DG, Kitabayashi I
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Journal Title
Nat Med
Volume: 16
Pages: 580-585
Peer Reviewed
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