Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia.

Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia.

Nature genetics (2012-12-25)

Kim De Keersmaecker, Zeynep Kalender Atak, Ning Li, Carmen Vicente, Stephanie Patchett, Tiziana Girardi, Valentina Gianfelici, Ellen Geerdens, Emmanuelle Clappier, Michaël Porcu, Idoya Lahortiga, Rossella Lucà, Jiekun Yan, Gert Hulselmans, Hilde Vranckx, Roel Vandepoel, Bram Sweron, Kris Jacobs, Nicole Mentens, Iwona Wlodarska, Barbara Cauwelier, Jacqueline Cloos, Jean Soulier, Anne Uyttebroeck, Claudia Bagni, Bassem A Hassan, Peter Vandenberghe, Arlen W Johnson, Stein Aerts, Jan Cools

PMID23263491

RÉSUMÉ

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.