Journal
NATURE GENETICS
Volume 45, Issue 2, Pages 186-190Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2508
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Funding
- KU Leuven [PF/10/016 SymBioSys]
- FWO-Vlaanderen [G.0546.11, G.0704.11N]
- Foundation against Cancer [SCIE2006-34, 2010-154]
- European Research Council (ERC)
- Federal Office for Scientific, Technical and Cultural Affairs, Belgium
- Ministry of Health, Cancer Plan
- French program Carte d'Identite des Tumeurs (CIT, Ligue Contre le Cancer)
- Canceropole d'Ile de France
- US National Institutes of Health (NIH) [GM53655]
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T-cell acute lymphoblastic leukemia (T-ALL) is caused by the cooperation of multiple oncogenic lesions(1,2). 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(3). 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.
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