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.