Point mutations of the RUNx1/AML1 gene in sporadic and familial myeloid leukemias.
The RUNX1/AML1 gene is known to be the most frequent target for chromosomal translocation in leukemia. In addition, recent studies have demonstrated point mutations in the RUNX1 gene as an another mode of genetic lesion resulting in leukemia. Of particular interest, sporadic point mutations of biallelic type are found in a tight association with either the acute myelogenous leukemia (AML) MO subtype or trisomy 21. Germline mutations give rise to a familial platelet disorder that results in a predisposition to acute myelogenous leukemia (FPD/AML). Most of the RUNX1 mutants were defective in DNA binding but still active in beta binding, a characteristic that is consistent with the 3-dimensional structural findings and may explain the dominant inhibitory effects. Although genuine haploinsufficiency of RUNX1 was observed in some cases, a greater majority of mutant RUNX1 proteins may also act in a dominant-negative manner, possibly creating a higher propensity for leukemia development. The stronger dominant-negative effect was also deduced to be the major mechanism of the chimeric genes created by chromosomal translocations. The decrement of RUNXI activity may be a common underlying cause for RUNX1-related leukemias. However, because these RUNX1 abnormalities per se are insufficient for leukemogenesis, cooperating genetic alteration(s) should be intensively sought for further mechanistic insights and future clinical applications.
Osato
M
M
Department of Viral Oncology, Institute for Virus Research, Kyoto University, Japan.
Yanagida
M
M
Shigesada
K
K
Ito
Y
Y
D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics*; D008954:Models, Biological; D017354:Point Mutation; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors