Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia Journal Article


Authors: Topka, S.; Vijai, J.; Walsh, M. F.; Jacobs, L.; Maria, A.; Villano, D.; Gaddam, P.; Wu, G.; McGee, R. B.; Quinn, E.; Inaba, H.; Hartford, C.; Pui, C. H.; Pappo, A.; Edmonson, M.; Zhang, M. Y.; Stepensky, P.; Steinherz, P.; Schrader, K.; Lincoln, A.; Bussel, J.; Lipkin, S. M.; Goldgur, Y.; Harit, M.; Stadler, Z. K.; Mullighan, C.; Weintraub, M.; Shimamura, A.; Zhang, J.; Downing, J. R.; Nichols, K. E.; Offit, K.
Article Title: Germline ETV6 mutations confer susceptibility to acute lymphoblastic leukemia and thrombocytopenia
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. © 2015 Topka et al.
Keywords: clinical article; controlled study; human cell; single nucleotide polymorphism; gene deletion; mutant protein; phenotype; allele; gene targeting; cancer susceptibility; gene expression; thrombocytopenia; genetic variability; gene function; genetic transcription; mutational analysis; acute lymphoblastic leukemia; oncogene; myelodysplastic syndrome; gene rearrangement; transcription regulation; heterozygosity; leukemia cell; leukemogenesis; acute myeloblastic leukemia; mean corpuscular volume; dna sequence; human relation; nuclear localization signal; germline mutation; rb1 gene; chromosome band; transcription factor pax5; human; article; btg1 gene; etv6 oncogene; ikzf1 gene; kindred; pax5 gene
Journal Title: PLoS Genetics
Volume: 11
Issue: 6
ISSN: 1553-7390
Publisher: Public Library of Science  
Date Published: 2015-06-23
Start Page: e1005262
Language: English
DOI: 10.1371/journal.pgen.1005262
PROVIDER: scopus
PMCID: PMC4477877
PUBMED: 26102509
DOI/URL:
Notes: Export Date: 2 September 2015 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    496 Offit
  2. Zsofia Kinga Stadler
    139 Stadler
  3. Yehuda Goldgur
    24 Goldgur
  4. Vijai Joseph
    113 Joseph
  5. Peter G Steinherz
    161 Steinherz
  6. Danylo Julian Villano
    13 Villano
  7. Lauren Michelle Jacobs
    10 Jacobs
  8. Ann   Maria
    7 Maria
  9. Anne Gunning Lincoln
    14 Lincoln
  10. Sabine   Topka
    6 Topka
  11. Pragna   Gaddam
    9 Gaddam