Journal Article

Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy

Schwartz, Bradford S, Coats, Scott A, Basom, Ryan S, Walsh, Tom, Abkowitz, Janis L, Delrow, Jeffrey J, Gulsuner, Suleyman, Sanchez-Bonilla, Marilyn, Loeb, Keith R, Neistadt, Barbara, Hofmann, Inga, Lindsley, R Coleman, Shimamura, Akiko, Churpek, Jane E, Marquez, Rafael, Mariani, Christopher J, King, Mary-Claire, Forouhar, Melissa, Zhang, Michael Y, Williams, David A, Godley, Lucy A, Lee, Ming K, Pritchard, Colin C, Keel, Siobán B, Gyurkocza, Boglarka, Horwitz, Marshall S

2015

Overview

Akiko Shimamura and colleagues report the identification of dominant-negative germline variants in ETV6 that cause thrombocytopenia and hematologic malignancies in the affected members of three families. All three mutations alter conserved amino acids in the transcriptional repressor encoded by ETV6 and affect its DNA binding. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/44 / 14 / 14/63 / 38 / 38/91 / 45 / 45/23 / 692/308/2056 / 692/699/1541 / 692/699/1541/1990/1673 / 82 / 82/83 / Agriculture / Amino acids / Animal Genetics and Genomics / Binding sites / Biomedicine / Blood diseases / Bone marrow / Cancer Research / Cell Proliferation / Deoxyribonucleic acid / DNA / ETS Translocation Variant 6 Protein / Exons - genetics / Female / Gene Function / Gene mutations / Genes, Reporter / Genetic aspects / Germ-Line Mutation / Health aspects / HeLa Cells / Hematologic Neoplasms - genetics / Human Genetics / Humans / letter / Leukemia / Male / Medical research / Models, Molecular / Molecular Sequence Data / Mutation / Mutation, Missense / Oncogenes / Pedigree / Protein Structure, Tertiary / Proto-Oncogene Proteins c-ets - genetics / Recombinant Proteins / Repressor Proteins - genetics / Sequence Analysis, RNA / Thrombocytopenia / Thrombocytopenia - genetics