Germline GATA1s generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype.

Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s generating mutations result in congenital anemia in males. We report on two unrelated families harboring germline GATA1s generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy or tetrasomy 21. The leukemia characteristics overlapped those of myeloid leukemia of Down syndrome including age of onset of less than 4 years, unique immunophenotype, complex karyotype, gene expression pattern, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is unique functional cooperatively between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s generating mutations should be included among those associated with familial myelodysplastic syndrome and leukemia predisposition.