Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia

• Published in: PLoS genetics Vol. 11; no. 6; p. e1005262
• Main Authors: Topka, Sabine, Vijai, Joseph, Walsh, Michael F, Jacobs, Lauren, Maria, Ann, Villano, Danylo, Gaddam, Pragna, Wu, Gang, McGee, Rose B, Quinn, Emily, Inaba, Hiroto, Hartford, Christine, Pui, Ching-Hon, Pappo, Alberto, Edmonson, Michael, Zhang, Michael Y, Stepensky, Polina, Steinherz, Peter, Schrader, Kasmintan, Lincoln, Anne, Bussel, James, Lipkin, Steve M, Goldgur, Yehuda, Harit, Mira, Stadler, Zsofia K, Mullighan, Charles, Weintraub, Michael, Shimamura, Akiko, Zhang, Jinghui, Downing, James R, Nichols, Kim E, Offit, Kenneth
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-06-2015; Public Library of Science (PLoS)
• Subjects: Amino Acid Sequence; Cancer; Case-Control Studies; ETS Translocation Variant 6 Protein; Genes; Germ-Line Mutation; HeLa Cells; Humans; Leukemia; Molecular Sequence Data; Mutation; Mutation, Missense; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Proteins; Proto-Oncogene Proteins c-ets - chemistry; Proto-Oncogene Proteins c-ets - genetics; Proto-Oncogene Proteins c-ets - metabolism; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; Thrombocytopenia - genetics; Transcription factors
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1005262

Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition.