2009 Fiscal Year Final Research Report
Study for regulatory mechanism of normal and leukemic stem cells through transcription factors
| Project/Area Number |
19390268
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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 Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East |
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Principal Investigator |
KITABAYASHI Issay National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East, 分子腫瘍学部, 部長 (20261175)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGATA Kazutsune 国立がんセンター(研究所及び東病院臨床開発センター), 分子腫瘍学部, 研究員 (70311412)
ROKUDAI Susumu 国立がんセンター(研究所及び東病院臨床開発センター), 分子腫瘍学部, 研究員 (50469970)
YOSHIDA Hitoshi 国立がんセンター(研究所及び東病院臨床開発センター), 分子腫瘍学部, 室長 (10506710)
WATANABE Toshio 奈良女子大学, 大学院・人間文化研究科, 教授 (60201208)
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| Project Period (FY) |
2007 – 2009
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| Keywords | 幹細胞 / 白血病 / 転写制御 |
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| Research Abstract |
MOZ (MOnocytic leukemia Zinc finger protein) and MORF (MOz Related Factor), Myst-type histone acetyltransferases, are involved in chromosome translocations associated with FAB-M4/5 subtypes of acute myeloid leukemia. We have reported that MOZ is essential for hematopoietic cell development and self-renewal of hematopoietic stem cells. To elucidate the roles of MORF in normal and malignant hematopoiesis, we generated Morf-deficient mice. Morf--/- mice were smaller than their wild-type littermates and died within 4 weeks after birth. In Morf--/- fetal liver, Flt3-negative KSL (c-Kit+, Sca-1+, Lineage-) cells containing hematopoietic stem cells are decreased. When fetal liver cells were transplanted into irradiated recipient mice, MORF-/- cells less efficiently reconstituted hematopoiesis than wild-type cells. Additionally, bone marrow cells reconstituted with MORF-/- cells rarely contributed to hematopoiesis in secondary transplants. To reveal interaction between MORF and MOZ, we generated double heterozygous (Moz+/- Morf+/-) mouse. Double heterozygous mouse was also smaller than wild-type littermates and died at least 4 weeks after birth. Numbers of KSL cells, especially Flt3- KSL cells and common myeloid progenitors were decreased in the double heterozygous fetal liver. The double heterozygous fetal liver cells also displayed less activity to reconstitute hematopoiesis than MOZ+/- or MORF+/- cells. These results suggest that MORF as well as MOZ plays important roles in self-renewal of hematopoietic stem cells.
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[Journal Article] 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. PU.
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Journal Title
Nat Med 16
Pages: 580-585
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