dc.contributor.author | Abdel-Wahab, Omar | en_US |
dc.contributor.author | Gao, Jie | en_US |
dc.contributor.author | Adli, Mazhar | en_US |
dc.contributor.author | Dey, Anwesha | en_US |
dc.contributor.author | Trimarchi, Thomas | en_US |
dc.contributor.author | Chung, Young Rock | en_US |
dc.contributor.author | Kuscu, Cem | en_US |
dc.contributor.author | Hricik, Todd | en_US |
dc.contributor.author | Ndiaye-Lobry, Delphine | en_US |
dc.contributor.author | LaFave, Lindsay M. | en_US |
dc.contributor.author | Koche, Richard | en_US |
dc.contributor.author | Shih, Alan H. | en_US |
dc.contributor.author | Guryanova, Olga A. | en_US |
dc.contributor.author | Kim, Eunhee | en_US |
dc.contributor.author | Li, Sheng | en_US |
dc.contributor.author | Pandey, Suveg | en_US |
dc.contributor.author | Shin, Joseph Y. | en_US |
dc.contributor.author | Telis, Leon | en_US |
dc.contributor.author | Liu, Jinfeng | en_US |
dc.contributor.author | Bhatt, Parva K. | en_US |
dc.contributor.author | Monette, Sebastien | en_US |
dc.contributor.author | Zhao, Xinyang | en_US |
dc.contributor.author | Mason, Christopher E. | en_US |
dc.contributor.author | Park, Christopher Y. | en_US |
dc.contributor.author | Bernstein, Bradley E. | en_US |
dc.contributor.author | Aifantis, Iannis | en_US |
dc.contributor.author | Levine, Ross L. | en_US |
dc.date.accessioned | 2014-07-07T18:14:40Z | |
dc.date.issued | 2013 | en_US |
dc.identifier.citation | Abdel-Wahab, O., J. Gao, M. Adli, A. Dey, T. Trimarchi, Y. R. Chung, C. Kuscu, et al. 2013. “Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo.” The Journal of Experimental Medicine 210 (12): 2641-2659. doi:10.1084/jem.20131141. http://dx.doi.org/10.1084/jem.20131141. | en |
dc.identifier.issn | 0022-1007 | en |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406978 | |
dc.description.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. | en |
dc.language.iso | en_US | en |
dc.publisher | The Rockefeller University Press | en |
dc.relation.isversionof | doi:10.1084/jem.20131141 | en |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832937/pdf/ | en |
dash.license | LAA | en_US |
dc.title | Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo | en |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en |
dc.relation.journal | The Journal of Experimental Medicine | en |
dash.depositing.author | Bernstein, Bradley E. | en_US |
dc.date.available | 2014-07-07T18:14:40Z | |
dc.identifier.doi | 10.1084/jem.20131141 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | Bernstein, Bradley | |