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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Abnormalities, Multiple / etiology*
  • Abnormalities, Multiple / genetics
  • Animals
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Epigenesis, Genetic
  • Female
  • Gene Deletion
  • Germ-Line Mutation
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Myelodysplastic Syndromes / etiology*
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / pathology
  • Phenotype
  • Pregnancy
  • Protein Binding
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics
  • Repressor Proteins / deficiency*
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism

Substances

  • ASXL1 protein, human
  • Asxl1 protein, mouse
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Tet2 protein, mouse