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

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

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International Radiation Information Center, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.


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.

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