Loss of Asxl2 leads to myeloid malignancies in mice

被引：25

作者：

Li, Jianping ^{[1
]}

He, Fuhong ^{[2
]}

Zhang, Peng ^{[1
]}

Chen, Shi ^{[1
]}

Shi, Hui ^{[1
,3
,4
,5
]}

Sun, Yanling ^{[2
,6
]}

Guo, Ying ^{[1
]}

Yang, Hui ^{[1
]}

Man, Na ^{[1
]}

Greenblatt, Sarah ^{[1
]}

Li, Zhaomin ^{[1
]}

Guo, Zhengyu ^{[7
,8
]}

Zhou, Yuan ^{[3
,4
,5
]}

Wang, Lan ^{[1
]}

Morey, Lluis ^{[1
]}

Williams, Sion ^{[1
]}

Chen, Xi ^{[1
,9
]}

Wang, Qun-Tian ^{[10
]}

Nimer, Stephen D. ^{[1
]}

Yu, Peng ^{[7
,8
]}

Wang, Qian-Fei ^{[2
,6
]}

Xu, Mingjiang ^{[1
]}

Yang, Feng-Chun ^{[1
]}

机构：

[1] Univ Miami, Miller Sch Med, Dept Biochem & Mol Biol, Sylvester Comprehens Canc Ctr, 1011 NW 15th St,Room 417, Miami, FL 33136 USA

[2] Chinese Acad Sci, Beijing Inst Genom, Collaborat Innovat Ctr Genet & Dev, Key Lab Genom & Precis Med, Beijing 100101, Peoples R China

[3] Chinese Acad Med Sci, State Key Lab Expt Hematol, Inst Hematol, Tianjin 300020, Peoples R China

[4] Chinese Acad Med Sci, Blood Dis Hosp, Tianjin 300020, Peoples R China

[5] Peking Union Med Coll, Tianjin 300020, Peoples R China

[6] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[7] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA

[8] Texas A&M Univ, TEES AgriLife Ctr Bioinformat & Genom Syst Engn, College Stn, TX 77843 USA

[9] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Miami, FL 33136 USA

[10] Univ Illinois, Dept Biol Sci, Chicago, IL 60607 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

CHIP-SEQ DATA; HEMATOPOIETIC STEM-CELLS; MYELODYSPLASTIC SYNDROMES; MURINE HOMOLOG; GENE ASXL1; LEUKEMIA; POLYCOMB; EXPRESSION; MUTATIONS; CANCER;

D O I：

10.1038/ncomms15456

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

ASXL2 is frequently mutated in acute myeloid leukaemia patients with t(8; 21). However, the roles of ASXL2 in normal haematopoiesis and the pathogenesis of myeloid malignancies remain unknown. Here we show that deletion of Asxl2 in mice leads to the development of myelodysplastic syndrome (MDS)-like disease. Asxl2(-/-) mice have an increased bone marrow (BM) long-term haematopoietic stem cells (HSCs) and granulocyte-macrophage progenitors compared with wild-type controls. Recipients transplanted with Asxl2(-/-) and Asxl2(+/-) BM cells have shortened lifespan due to the development of MDS-like disease or myeloid leukaemia. Paired daughter cell assays demonstrate that Asxl2 loss enhances the self-renewal of HSCs. Deletion of Asxl2 alters the expression of genes critical for HSC self-renewal, differentiation and apoptosis in Lin(-) cKit(+) cells. The altered gene expression is associated with dysregulated H3K27ac and H3K4me1/2. Our study demonstrates that ASXL2 functions as a tumour suppressor to maintain normal HSC function.

引用

页数：14

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