Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice

Blood. 2014 Jan 23;123(4):541-53. doi: 10.1182/blood-2013-05-500272. Epub 2013 Nov 19.


ASXL1 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies, and its alterations are associated with poor prognosis. De novo ASXL1 mutations cause Bohring-Opitz syndrome characterized by multiple congenital malformations. We show that Asxl1 deletion in mice led to developmental abnormalities including dwarfism, anophthalmia, and 80% embryonic lethality. Surviving Asxl1(-/-) mice lived for up to 42 days and developed features of myelodysplastic syndrome (MDS), including dysplastic neutrophils and multiple lineage cytopenia. Asxl1(-/-) mice had a reduced hematopoietic stem cell (HSC) pool, and Asxl1(-/-) HSCs exhibited decreased hematopoietic repopulating capacity, with skewed cell differentiation favoring granulocytic lineage. Asxl1(+/-) mice also developed mild MDS-like disease, which could progress to MDS/myeloproliferative neoplasm, demonstrating a haploinsufficient effect of Asxl1 in the pathogenesis of myeloid malignancies. Asxl1 loss led to an increased apoptosis and mitosis in Lineage(-)c-Kit(+) (Lin(-)c-Kit(+)) cells, consistent with human MDS. Furthermore, Asxl1(-/-) Lin(-)c-Kit(+) cells exhibited decreased global levels of H3K27me3 and H3K4me3 and altered expression of genes regulating apoptosis (Bcl2, Bcl2l12, Bcl2l13). Collectively, we report a novel ASXL1 murine model that recapitulates human myeloid malignancies, implying that Asxl1 functions as a tumor suppressor to maintain hematopoietic cell homeostasis. Future work is necessary to clarify the contribution of microenvironment to the hematopoietic phenotypes observed in the constitutional Asxl1(-/-) mice.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Bone Marrow Cells / cytology
  • Cell Differentiation
  • Cell Lineage
  • Cell Proliferation
  • Crosses, Genetic
  • Disease Models, Animal
  • Gene Deletion
  • Green Fluorescent Proteins / metabolism
  • Hematopoiesis
  • Hematopoietic Stem Cells / cytology
  • Homeostasis
  • Homozygote
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitosis
  • Mutation*
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / metabolism
  • Phenotype
  • Repressor Proteins / genetics*
  • Repressor Proteins / physiology*


  • Asxl1 protein, mouse
  • Repressor Proteins
  • Green Fluorescent Proteins