High frequency of RUNX1biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder

Familial platelet disorder (FPD), a rare autosomal dominant disorder characterized by quantitative and qualitative platelet abnormalities, is considered as a model of genetic predisposition to acute myeloid leukemia (AML). So far, monoallelic RUNX1germline mutations have been found in 19 of 20 families with reported FPD, and the analysis of blast cells from only 5 patients at acute leukemia (AL) stage has shown no additional RUNX1abnormality. Here, we performed RUNX1analysis at constitutional and somatic levels in 8 persons with FPD who developed AL from 4 independent families. In addition to the germline RUNX1mutation, we identified a second RUNX1alteration in 6 AML cases (acquired point mutations in 4 cases and duplication of the altered RUNX1allele associated with acquired trisomy 21 in 2 other cases). Although haploinsufficiency of RUNX1causes FPD, our findings suggest that a second genetic event involving RUNX1is often associated with progression to AML.