Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia

Sabine Topka, Joseph Vijai, Michael F. Walsh, Lauren Jacobs, Ann Maria, Danylo Villano, Pragna Gaddam, Gang Wu, Rose B. McGee, Emily Quinn, Hiroto Inaba, Christine Hartford, Ching hon Pui, Alberto Pappo, Michael Edmonson, Michael Y. Zhang, Polina Stepensky, Peter Steinherz, Kasmintan Schrader, Anne LincolnJames Bussel, Steve M. Lipkin, Yehuda Goldgur, Mira Harit, Zsofia K. Stadler, Charles Mullighan, Michael Weintraub, Akiko Shimamura, Jinghui Zhang, James R. Downing, Kim E. Nichols, Kenneth Offit

Research output: Contribution to journalArticlepeer-review

113 Scopus citations


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.

Original languageEnglish
Article numbere1005262
JournalPLoS Genetics
Issue number6
StatePublished - 1 Jul 2015
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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