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.
Pubmed ID: 24218140 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
GenomeNet is a Japanese network of database and computational services for genome research and related research areas in biomedical sciences, operated by the Kyoto University Bioinformatics Center. GenomeNet was established in September 1991 under the Human Genome Program of the then Ministry of Education, Science and Culture (Monbusho). The GenomeNet service has been developed by the Kanehisa Laboratory in Kyoto University as part of the research projects. GenomeNet is operated using the Supercomputer System of the Institute for Chemical Research, Kyoto University. LinkDB is supported by the National Bioscience Database Center of the Japan Science and Technology Agency.
View all literature mentionsCore offers comprehensive light and electron microscopy technologies. Our scientists use light microscopes and electron microscopes at resolutions ranging from centimeters to angstroms, providing clear and detailed images.We assist at every stage of your experiment, offering research-design consultation and instrument training, as well as guidance in study execution, analysis, and presentation for publication.
View all literature mentionslaboratory mouse with name 129/SvEv from MGI.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentions