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PLoS Genet. 2015 Jun 23;11(6):e1005262. doi: 10.1371/journal.pgen.1005262. eCollection 2015 Jun.

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

Author information

1
Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America; Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, New York, United States of America.
2
St Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, United States of America.
3
Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America.
4
Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington, United States of America.
5
Pediatric Hematology/Oncology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
6
University of British Columbia, Vancouver, British Columbia, Canada.
7
Weill Cornell Medical College, New York, New York, United States of America.
8
Structural Biology Program, Sloan Kettering Institute, New York, New York, United States of America.
9
Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington, United States of America; Seattle Children's Hospital, Seattle, Washington, United States of America.
10
Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, United States of America; Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, New York, United States of America; Weill Cornell Medical College, New York, New York, United States of America.

Abstract

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.

PMID:
26102509
PMCID:
PMC4477877
DOI:
10.1371/journal.pgen.1005262
[Indexed for MEDLINE]
Free PMC Article
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