title: Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia.
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.
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Zeynep Kalender
authors.initials: ZK
authors.lastname: Atak
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Carmen
authors.initials: C
authors.lastname: Vicente
authors.forename: Stephanie
authors.initials: S
authors.lastname: Patchett
authors.forename: Tiziana
authors.initials: T
authors.lastname: Girardi
authors.forename: Valentina
authors.initials: V
authors.lastname: Gianfelici
authors.forename: Ellen
authors.initials: E
authors.lastname: Geerdens
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clappier
authors.forename: Michaël
authors.initials: M
authors.lastname: Porcu
authors.forename: Idoya
authors.initials: I
authors.lastname: Lahortiga
authors.forename: Rossella
authors.initials: R
authors.lastname: Lucà
authors.forename: Jiekun
authors.initials: J
authors.lastname: Yan
authors.forename: Gert
authors.initials: G
authors.lastname: Hulselmans
authors.forename: Hilde
authors.initials: H
authors.lastname: Vranckx
authors.forename: Roel
authors.initials: R
authors.lastname: Vandepoel
authors.forename: Bram
authors.initials: B
authors.lastname: Sweron
authors.forename: Kris
authors.initials: K
authors.lastname: Jacobs
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
authors.forename: Barbara
authors.initials: B
authors.lastname: Cauwelier
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Anne
authors.initials: A
authors.lastname: Uyttebroeck
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Hassan
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Arlen W
authors.initials: AW
authors.lastname: Johnson
authors.forename: Stein
authors.initials: S
authors.lastname: Aerts
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
mesh_terms: D000818:Animals; D001483:Base Sequence; D004331:Drosophila melanogaster; D059472:Exome / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D011132:Polyribosomes / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D034622:RNA Interference; D000080882:Ribosomal Protein L10; D012269:Ribosomal Proteins / Q000235:genetics*; D012441:Saccharomyces cerevisiae; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C466622:CNOT3 protein, human; C000630686:RPL10 protein, human; D012269:Ribosomal Proteins; C000630690:Rpl10 protein, mouse; D014157:Transcription Factors; C549166:ribosomal protein L5, human