Germline missense ETV6 mutations are associated with thrombocytopenia and hematologic malignancies.
Major finding: Germline missense ETV6 mutations are associated with thrombocytopenia and hematologic malignancies.
Mechanism: Dominant-negative ETV6 mutants abrogate transcriptional repression and impair hematopoiesis.
Impact: Heterozygous ETV6 mutations may be an early driving event in malignant transformation.
The genetic alterations associated with predisposition to familial myelodysplastic syndrome (MDS) and acute leukemia remain largely unidentified. To understand the mechanisms underlying rare cases of familial MDS–leukemia, Zhang and colleagues studied a family with idiopathic familial thrombocytopenia and hematologic malignancies, and identified a heterozygous germline variant in the ETS variant 6 gene (ETV6), which encoded for p.Arg399Cys, in affected individuals. Further sequencing of individuals with genetically undefined familial thrombocytopenia and MDS or leukemia revealed two additional families with autosomal dominant transmission of ETV6 variants corresponding to p.Arg369Gln and p.Pro214Leu. Of note, recurrent somatic mutations of these same three amino acids have been reported in various cancers. Consistent with molecular modeling, the identified missense variants disrupted binding of the ETV6 transcriptional repressor to DNA. ETV6 mutation also reduced its nuclear localization and impaired ETV6-mediated transcriptional repression; coexpression of mutant ETV6 antagonized wild-type ETV6–driven repression in a dose-dependent fashion, indicating that ETV6 mutants act in a dominant-negative manner. Oligomerization-defective ETV6 mutant proteins failed to inhibit wild-type ETV6–mediated repression, suggesting that oligomerization is required for this dominant-negative function. Furthermore, expression of mutant ETV6 reduced the proliferation of CD34+ hematopoietic stem/progenitor cells and altered gene expression, in particular platelet-associated gene sets, demonstrating a role for ETV6 in hematopoiesis. In addition, evaluation of paired tumor and fibroblast samples from individuals with germline ETV6 mutation highlighted acquisition of additional mutations during malignant progression. Identification of germline missense ETV6 mutations associated with cancer predisposition suggests that ETV6 mutation may be an early initiating event in malignant transformation and supports the complementary analysis of familial cancer syndromes and cancer genome sequencing to identify driver mutations of malignancy.