Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy

MY Zhang, JE Churpek, SB Keel, T Walsh, MK Lee… - Nature …, 2015 - nature.com
MY Zhang, JE Churpek, SB Keel, T Walsh, MK Lee, KR Loeb, S Gulsuner, CC Pritchard…
Nature genetics, 2015nature.com
We report germline missense mutations in ETV6 segregating with the dominant transmission
of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a
new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse
hematologic neoplasms. Two variants, p. Arg369Gln and p. Arg399Cys, reside in the highly
conserved ETS DNA-binding domain. The third variant, p. Pro214Leu, lies within the internal
linker domain, which regulates DNA binding. These three amino acid sites correspond to …
Abstract
We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.
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