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 |
