Loss of Asxl2 leads to myeloid malignancies in mice

Jianping Li, Fuhong He, Peng Zhang, Shi Chen, Hui Shi, Yanling Sun, Ying Guo, Hui Yang, Na Man, Sarah Greenblatt, Zhaomin Li, Zhengyu Guo, Yuan Zhou, Lan Wang, Lluis Morey, Sion Williams, Xi Chen, Qun-Tian Wang, Stephen D. Nimer, Peng Yu, Qian-Fei Wang (), Mingjiang Xu () and Feng-Chun Yang ()
Additional contact information
Jianping Li: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Fuhong He: Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences
Peng Zhang: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Shi Chen: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Hui Shi: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Yanling Sun: Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences
Ying Guo: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Hui Yang: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Na Man: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Sarah Greenblatt: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Zhaomin Li: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Zhengyu Guo: and TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University
Yuan Zhou: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Lan Wang: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Lluis Morey: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Sion Williams: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Xi Chen: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Qun-Tian Wang: University of Illinois at Chicago
Stephen D. Nimer: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Peng Yu: and TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University
Qian-Fei Wang: Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences
Mingjiang Xu: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Feng-Chun Yang: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15456

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