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 p oint mutations in the RUNX1 gene as an another mode of genetic lesion resul ting in leukemia. Of particular interest, sporadic point mutations of biall elic type are found in a tight association with either the acute myelogenou s leukemia (AML) MO subtype or trisomy 21. Germline mutations give rise to a familial platelet disorder that results in a predisposition to acute myel ogenous leukemia (FPD/AML). Most of the RUNX1 mutants were defective in DNA binding but still active in beta binding, a characteristic that is consist ent with the 3-dimensional structural findings and may explain the dominant inhibitory effects. Although genuine haploinsufficiency of RUNX1 was obser ved in some cases, a greater majority of mutant RUNX1 proteins may also act in a dominant-negative manner, possibly creating a higher propensity for l eukemia development. The stronger dominant-negative effect was also deduced to be the major mechanism of the chimeric genes created by chromosomal tra nslocations. The decrement of RUNX1 activity may be a common underlying cau se 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. (C) 2001 The Japanese Society of Hematology.