期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 210, 期 12, 页码 2641-2659出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20131141
关键词
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资金
- Starr Cancer Consortium
- Gabrielle's Angel Fund
- National Institutes of Health (NIH) [1R01CA138234-01, 5R01CA173636-01]
- Leukemia and Lymphoma Society (LLS) Translational Research Program grant
- National Heart, Lung, and Blood Institute [5U01HL100395]
- NIH [R01CA133379, R01CA105129, 1R01CA173636, R01CA149655, 5R01CA173636]
- LLS Chemotherapy Foundation
- William Lawrence Blanche Hughes Foundation
- V Foundation for Cancer Research
- New York University [T32 CA009161]
- NIH K08 Clinical Investigator Award [1K08CA160647-01]
- US Department of Defense Postdoctoral Fellow Award in Bone Marrow Failure Research [W81XWH-12-1-0041]
- Josie Roberston Investigator Program
- Damon Runyon Clinical Investigator Award
- Evans Foundation
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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