Study for regulatory mechanism of normal and leukemic stem cells through transcription factors

转录因子对正常和白血病干细胞的调控机制研究

基本信息

批准号：
19390268
负责人：
KITABAYASHI Issay
金额：
$ 11.4万
依托单位：
National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2009
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19390268/
关键词：
幹細胞白血病転写制御造血幹細胞 MOZ PU.1 GATA 細胞分化 PML

项目摘要

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.

MOZ（单核细胞白血病锌指蛋白）和 MORF（MOz 相关因子）是 Myst 型组蛋白乙酰转移酶，参与与急性髓系白血病 FAB-M4/5 亚型相关的染色体易位。我们报道MOZ对于造血细胞发育和造血干细胞的自我更新至关重要。为了阐明 MORF 在正常和恶性造血中的作用，我们培育了 Morf 缺陷小鼠。 Morf--/- 小鼠比其野生型同窝小鼠小，并且在出生后 4 周内死亡。在 Morf--/- 胎儿肝脏中，含有造血干细胞的 Flt3 阴性 KSL（c-Kit+、Sca-1+、Lineage-）细胞减少。当胎儿肝细胞被移植到受辐射的受体小鼠体内时，MORF-/-细胞重建造血的效率低于野生型细胞。此外，用 MORF-/- 细胞重建的骨髓细胞很少有助于二次移植中的造血作用。为了揭示 MORF 和 MOZ 之间的相互作用，我们生成了双杂合 (Moz+/- Morf+/-) 小鼠。双杂合小鼠也比野生型同窝小鼠小，并且在出生后至少 4 周死亡。双杂合子胎肝中KSL细胞，尤其是Flt3-KSL细胞和共同髓系祖细胞的数量减少。双杂合胎儿肝细胞还表现出比MOZ+/-或MORF+/-细胞更低的重建造血活性。这些结果表明MORF和MOZ在造血干细胞的自我更新中发挥重要作用。