Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy Academic Article uri icon


MeSH Major

  • Hematologic Neoplasms
  • Proto-Oncogene Proteins c-ets
  • Repressor Proteins
  • Thrombocytopenia


  • 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.

publication date

  • January 2015



  • Academic Article



  • eng

PubMed Central ID

  • PMC4540357

Digital Object Identifier (DOI)

  • 10.1038/ng.3177

PubMed ID

  • 25581430

Additional Document Info

start page

  • 180

end page

  • 5


  • 47


  • 2