Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia.

TitleGermline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia.
Publication TypeJournal Article
Year of Publication2015
AuthorsTopka, S, Vijai, J, Walsh, MF, Jacobs, L, Maria, A, Villano, D, Gaddam, P, Wu, G, McGee, RB, Quinn, E, Inaba, H, Hartford, C, Pui, C-H, Pappo, A, Edmonson, M, Zhang, MY, Stepensky, P, Steinherz, P, Schrader, K, Lincoln, A, Bussel, J, Lipkin, SM, Goldgur, Y, Harit, M, Stadler, ZK, Mullighan, C, Weintraub, M, Shimamura, A, Zhang, J, Downing, JR, Nichols, KE, Offit, K
JournalPLoS Genet
Volume11
Issue6
Paginatione1005262
Date Published2015 Jun
ISSN1553-7404
Abstract

<p>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.</p>

DOI10.1371/journal.pgen.1005262
Alternate JournalPLoS Genet.
PubMed ID26102509
PubMed Central IDPMC4477877
Grant List5P30 CA08748-40 / CA / NCI NIH HHS / United States
CA178800 / CA / NCI NIH HHS / United States
CA21765 / CA / NCI NIH HHS / United States
CA36401 / CA / NCI NIH HHS / United States
GM92666 / GM / NIGMS NIH HHS / United States
P30 CA021765 / CA / NCI NIH HHS / United States
R24 DK099808 / DK / NIDDK NIH HHS / United States