A New Pathogenomic Mechanism In FPD/AML by a Constitutional T(16;21) Involving 16p13 ATF7IP2 and 21q22 RUNX1 Loci

Abstract 4851

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant disorder characterized by platelet abnormalities and a predisposition to acute myeloid leukemia (AML). FPD/AML is caused by inherited mutations in 21q22 RUNX1. Recent publications by us and others reported on RUNX1 copy number changes as a pathogenomic mechanism next to point mutations in diagnosing FPD/AML. Given the clinical heterogeneity of FPD/AML, the syndrome could be overlooked, and has resulted in the past in stem cell transplantation (SCT) of patients from affected siblings before detection of the inherited RUNX1 mutation.

Here we report on the identification of two novel missense mutations (G143R and Q235X), and a constitutional RUNX1 gene rearrangement as a result of a t(16;21)(p13;q22) as a novel pathogenomic mechanism in FPD/AML. The 16p13 breakpoint was confined to the ATF7IP2 (MCAF1) locus, a transcription factor associated with Sp1, which is involved in myeloid differentiation, and in proliferation in human cancer by epigenetic transcriptional control of Sp1-dependent maintenance of telomerase activity. This is the first report on genomic involvement of the ATF7IP2 locus in cancer. We will discuss ongoing studies to molecularly identify the breakpoints.

Our data indicate that in diagnosing FPD/AML FISH has to be performed for structural abnormalities along with sequencing and copy number analysis of RUNX1. Furthermore, this is the first report on a constitutional chromosome translocation with an oncogene rearrangement as a pathogenomic mechanism in a hematological malignancy.