Molecular pathways mediating MDS/AML with focus on AML1/RUNX1 point mutations

J Cell Physiol. 2009 Jul;220(1):16-20. doi: 10.1002/jcp.21769.


AML1/RUNX1 point mutations have been identified in myelodysplastic syndrome (MDS) and MDS-related acute myeloid leukemia (AML), or MDS/AML, and are distributed throughout the full length of AML1/RUNX1. Gene mutation is proposed to be one of the disease-defining genetic abnormalities of MDS/AML. Most of the mutants lose trans-activation potential, which leads to a loss of normal function indicating that AML1/RUNX1 dysfunction is one of the major pathogenic mechanisms of MDS/AML. However, N-terminal in-frame mutations (Ni-type) and C-terminal truncated mutations (Ct-type) of AML1/RUNX1 show a dominant-negative effect on the trans-activation activity, suggesting that these types of mutants may have some oncogenic potential in addition to the loss of normal function. The patients with Ni-type mutations have hypoplastic marrows with other genetic abnormalities, whereas the patients with Ct-type mutations display hyperplastic marrows without other mutations. Although biological analysis using a mouse bone marrow transplantation model transduced with Ni-type of D171N or Ct-type of S291fsX300 mutants has partially confirmed the oncogenic ability of AML1 mutants, it could not explain the mutant specific clinical features of MDS/AML. Biological analysis using human CD34(+) cells revealed that the two types exhibited distinct molecular mechanisms. Ni-type shows differentiation block without cell growth, but additional BMI-1-expression resulted in increased blastic cells. In contrast, Ct-type itself has proliferation ability. Thus, AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antigens, CD34 / analysis
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Gene Expression Regulation, Leukemic*
  • Genotype
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / pathology
  • Phenotype
  • Point Mutation*
  • Signal Transduction / genetics


  • Antigens, CD34
  • Core Binding Factor Alpha 2 Subunit
  • RUNX1 protein, human