Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo

Journal of Experimental Medicine - Tập 210 Số 12 - Trang 2641-2659 - 2013
Omar Abdel‐Wahab1,2,3,4,5, Jie Gao6,7, Mazhar Adli8, Anwesha Dey9,10,11, Thomas Trimarchi6,7, Young Rock Chung1,2,3,5, Cem Kuscu8, Todd Hricik1,2,3,5, Delphine Ndiaye‐Lobry6,7, Lindsay M. LaFave1,2,3,5, Richard P. Koche12,13,14, Alan H. Shih1,2,3,5, Olga A. Guryanova1,2,3,5, Eun Hee Kim1,2,3,5, Sheng Li15,16, Suveg Pandey1,2,3,5, Joseph Shin1,2,3,5, Leon Telis1,2,3,5, Jinfeng Liu9,10,11, Parva Bhatt1,2,3,5, Sébastien Monette17, Xinyang Zhao18, Christopher E. Mason15,16, Christopher Y. Park1,2,3,5, B Bernstein12,13,14, Iannis Aifantis6,7, Ross L. Levine19,20
1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 1 , 2 , 3 , and 4
2Gerstner Sloan-Kettering Graduate School of Biomedical Sciences 1 , 2 , 3 , and 4
3Human Oncology and Pathogenesis Program 1 , 2 , 3 , and 4
4Human Oncology and Pathogenesis Program, 2 Leukemia Service, 3 Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, and 4 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
5Leukemia Service 1 , 2 , 3 , and 4
6Department of Pathology, New York University School of Medicine, New York, NY 10016 5 and 6
7Howard Hughes Medical Institute 5 and 6
8Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908 7
9Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080 11 and 12
10Department of Molecular Biology 11 and 12
11Genentech, Inc.
12Broad Institute of MIT and Harvard, Cambridge, MA 02142 8
13Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 9 and 10
14Howard Hughes Medical Institute 9 and 10
15Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065 13 and 14
16Graduate School of Medical Sciences 13 and 14
17Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, and The Rockefeller University, New York, NY 10065 15
18Department of Biochemistry and Molecular Genetics, University of Alabama, Birmingham, AL 35294 16
19(Cornell University
20Memorial Sloan Kettering Cancer Center

Tóm tắt

Somatic Addition of Sex Combs Like 1 (ASXL1) mutations occur in 10–30% of patients with myeloid malignancies, most commonly in myelodysplastic syndromes (MDSs), and are associated with adverse outcome. Germline ASXL1 mutations occur in patients with Bohring-Opitz syndrome. Here, we show that constitutive loss of Asxl1 results in developmental abnormalities, including anophthalmia, microcephaly, cleft palates, and mandibular malformations. In contrast, hematopoietic-specific deletion of Asxl1 results in progressive, multilineage cytopenias and dysplasia in the context of increased numbers of hematopoietic stem/progenitor cells, characteristic features of human MDS. Serial transplantation of Asxl1-null hematopoietic cells results in a lethal myeloid disorder at a shorter latency than primary Asxl1 knockout (KO) mice. Asxl1 deletion reduces hematopoietic stem cell self-renewal, which is restored by concomitant deletion of Tet2, a gene commonly co-mutated with ASXL1 in MDS patients. Moreover, compound Asxl1/Tet2 deletion results in an MDS phenotype with hastened death compared with single-gene KO mice. Asxl1 loss results in a global reduction of H3K27 trimethylation and dysregulated expression of known regulators of hematopoiesis. RNA-Seq/ChIP-Seq analyses of Asxl1 in hematopoietic cells identify a subset of differentially expressed genes as direct targets of Asxl1. These findings underscore the importance of Asxl1 in Polycomb group function, development, and hematopoiesis.

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Journal of Experimental Medicine

Tập 210 Số 12

2641-2659

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