Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia

Abstract

The familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) represents a unique model to study leukemic progression. Whereas qualitative or quantitative platelet defects are a constant feature of the disease, the onset of the hematological malignancy can be very heterogeneous and the molecular mechanisms responsible for leukemia progression remain poorly understood. We analyzed a cohort of 25 individuals from 15 FPD/AML pedigrees for mutations in 44 AML-associated genes, including genes recently associated with germline or acquired RUNX1 aberrations such as CDC25C, GATA2 and ASXL1/2. Of the 25 patients, 13 were studied following acute leukemia development (10 with acute myeloid leukemia (AML) and 3 with T-cell acute lymphoblastic leukemia). Interestingly, a second, somatically acquired alteration in RUNX1 was found in nearly all patients who developed AML, including second mutation, copy neutral loss of heterozygosity or duplication of the RUNX1-mutated or -deleted allele. These latter two events were identified by analysis of the allelic ratio coupled with karyotype. Additional somatic mutations in genes implicated in signaling, RNA splicing or epigenetic regulation were also identified at leukemic transformation. Our findings suggest that biallelic RUNX1 alterations are crucial for AML development in FPD/AML.