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J Exp Med. 2013 Nov 18;210(12):2641-59. doi: 10.1084/jem.20131141. Epub 2013 Nov 11.

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

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1
Human 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.

Abstract

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.

PMID:
24218140
PMCID:
PMC3832937
DOI:
10.1084/jem.20131141
[Indexed for MEDLINE]
Free PMC Article

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