AML1 mutations induced MDS and MDS/AML in a mouse BMT model

Blood. 2008 Apr 15;111(8):4297-308. doi: 10.1182/blood-2007-01-068346. Epub 2008 Jan 11.


Myelodysplastic syndrome (MDS) is a hematopoietic stem-cell disorder characterized by trilineage dysplasia and susceptibility to acute myelogenous leukemia (AML). Analysis of molecular basis of MDS has been hampered by the heterogeneity of the disease. Recently, mutations of the transcription factor AML1/RUNX1 have been identified in 15% to 40% of MDS-refractory anemia with excess of blasts (RAEB) and MDS/AML. We performed mouse bone marrow transplantation (BMT) using bone marrow cells transduced with the AML1 mutants. Most mice developed MDS and MDS/AML-like symptoms within 4 to 13 months after BMT. Interestingly, among integration sites identified, Evi1 seemed to collaborate with an AML1 mutant harboring a point mutation in the Runt homology domain (D171N) to induce MDS/AML with an identical phenotype characterized by marked hepatosplenomegaly, myeloid dysplasia, leukocytosis, and biphenotypic surface markers. Collaboration between AML1-D171N and Evi1 was confirmed by a BMT model where coexpression of AML1-D171N and Evi1 induced acute leukemia of the same phenotype with much shorter latencies. On the other hand, a C-terminal truncated AML1 mutant (S291fsX300) induced pancytopenia with erythroid dysplasia in transplanted mice, followed by progression to MDS-RAEB or MDS/AML. Thus, we have developed a useful mouse model of MDS/AML that should help in the understanding of the molecular basis of MDS and the progression of MDS to overt leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Cell Count
  • Bone Marrow Transplantation*
  • Cell Lineage
  • Core Binding Factor Alpha 2 Subunit / chemistry
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Erythroid Cells / pathology
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukocytosis / pathology
  • Leukopenia / pathology
  • MDS1 and EVI1 Complex Locus Protein
  • Mice
  • Mice, Inbred C57BL
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Myelodysplastic Syndromes / genetics*
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Pancytopenia / pathology
  • Proto-Oncogenes
  • Spleen / pathology
  • Transcription Factors / metabolism
  • Transduction, Genetic


  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • MDS1 and EVI1 Complex Locus Protein
  • Mecom protein, mouse
  • Mutant Proteins
  • Transcription Factors