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

K De Keersmaecker, ZK Atak, N Li, C Vicente… - Nature …, 2013 - nature.com
K De Keersmaecker, ZK Atak, N Li, C Vicente, S Patchett, T Girardi, V Gianfelici, E Geerdens…
Nature genetics, 2013nature.com
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 …
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.
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