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

Omar Abdel-Wahab, Jie Gao, Mazhar Adli, Anwesha Dey, Thomas Trimarchi, Young Rock Chung, Cem Kuscu, Todd Hricik, Delphine Ndiaye-Lobry, Lindsay M. LaFave, Richard Koche, Alan H. Shih, Olga A. Guryanova, Eunhee Kim, Sheng Li, Suveg Pandey, Joseph Y. Shin, Leon Telis, Jinfeng Liu, Parva K. BhattSebastien Monette, Xinyang Zhao, Christopher E. Mason, Christopher Y. Park, Bradley E. Bernstein, Iannis Aifantis, Ross L. Levine

Research output: Contribution to journalArticlepeer-review

258 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2641-2659
Number of pages19
JournalJournal of Experimental Medicine
Issue number12
StatePublished - Nov 2013
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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