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- Title
Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia.
- Authors
De Keersmaecker, Kim; Atak, Zeynep Kalender; Li, Ning; Vicente, Carmen; Patchett, Stephanie; Girardi, Tiziana; Gianfelici, Valentina; Geerdens, Ellen; Clappier, Emmanuelle; Porcu, Michaël; Lahortiga, Idoya; Lucà, Rossella; Yan, Jiekun; Hulselmans, Gert; Vranckx, Hilde; Vandepoel, Roel; Sweron, Bram; Jacobs, Kris; Mentens, Nicole; Wlodarska, Iwona
- Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is caused by the cooperation of multiple oncogenic lesions. We used exome sequencing on 67 T-ALLs to gain insight into the mutational spectrum in these leukemias. We detected protein-altering mutations in 508 genes, with an average of 8.2 mutations in pediatric and 21.0 mutations in adult T-ALL. Using stringent filtering, we predict seven new oncogenic driver genes in T-ALL. We identify CNOT3 as a tumor suppressor mutated in 7 of 89 (7.9%) adult T-ALLs, and its knockdown causes tumors in a sensitized Drosophila melanogaster model. In addition, we identify mutations affecting the ribosomal proteins RPL5 and RPL10 in 12 of 122 (9.8%) pediatric T-ALLs, with recurrent alterations of Arg98 in RPL10. Yeast and lymphoid cells expressing the RPL10 Arg98Ser mutant showed a ribosome biogenesis defect. Our data provide insights into the mutational landscape of pediatric versus adult T-ALL and identify the ribosome as a potential oncogenic factor.
- Subjects
NUCLEOTIDE sequence; GENETIC mutation; RIBOSOMES; T cells; LYMPHOBLASTIC leukemia; ORIGIN of life; DROSOPHILA melanogaster
- Publication
Nature Genetics, 2013, Vol 45, Issue 2, p186
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.2508