De Keersmaecker, K., Atak, Z.K., Li, N., Vicente, C., Patchett, S., Girardi, T., Gianfelici, V., Geerdens, E., Clappier, E., Porcu, M., Lahortiga, I., Lucà, R., Yan, J., Hulselmans, G., Vranckx, H., Vandepoel, R., Sweron, B., Jacobs, K., Mentens, N., Wlodarska, I., Cauwelier, B., Cloos, J., Soulier, J., Uyttebroeck, A., Bagni, C., Hassan, B.A., Vandenberghe, P., Johnson, A.W., Aerts, S., Cools, J. (2013). Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia.  Nat. Genet. 45(2): 186--190.

FBrf0220606

Research paper

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.

PMC5547913 (PMC) (EuropePMC)