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 lesions1,2. 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 model3. 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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Figure 1: Correlation between the age of the affected individual and mutation number and type.
Figure 2: Overview of mutations in 15 identified candidate T-ALL driver genes in 67 samples from affected individuals.
Figure 3: Overview of mutations in RPL10, RPL5 and CNOT3.
Figure 4: Cellular effects of the RPL10 p.Arg98Ser alteration.
Figure 5: Reduced Not3 expression promotes tumor development in a Drosophila sensitized background.

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Acknowledgements

This work was supported by grants from KU Leuven (concerted action grant to J. Cools and P.V. and PF/10/016 SymBioSys to J. Cools and S.A.), FWO-Vlaanderen (G.0546.11 to J. Cools, P.V., S.A. and A.U. and G.0704.11N to S.A.), the Foundation against Cancer (SCIE2006-34 to J. Cools and 2010-154 to S.A.), a European Research Council (ERC) starting grant (J. Cools), the Interuniversity Attraction Poles (IAP) granted by the Federal Office for Scientific, Technical and Cultural Affairs, Belgium (J. Cools and P.V.), a grant from the Ministry of Health, Cancer Plan (J. Cools, P.V. and S.A.), a grant from the French program Carte d'Identité des Tumeurs (CIT, Ligue Contre le Cancer) and from Canceropole d'Ile de France (J.S.), and a grant from the US National Institutes of Health (NIH; GM53655 to A.W.J. and S.P.). K.D.K. is a postdoctoral researcher, and P.V. is a senior clinical investigator of FWO-Vlaanderen.

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All authors contributed to the writing of the manuscript. K.D.K., Z.K.A., N.L., C.B., B.A.H. and A.W.J. designed and performed experiments and analyzed data. C.V. and J.Y. performed and analyzed Not3 Drosophila experiments. S.P. performed and analyzed Rpl10 yeast studies. R.L. performed and analyzed polysome profiling experiments. T.G., V.G., E.G., M.P., I.L., G.H., E.C., R.V., B.S., K.J., N.M. and I.W. performed experiments and analyzed data. H.V., B.C., J. Cloos, J.S., A.U. and P.V. collected samples and analyzed data. S.A. and J. Cools supervised the project, designed experiments and analyzed data.

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Correspondence to Stein Aerts or Jan Cools.

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The authors declare competing financial interests: N.L. is employed by BGI.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–9 and Supplementary Tables 1–4, 6 and 8–11 (PDF 6404 kb)

Supplementary Table 5

Protein-altering (A) somatic SNVs and (B) somatic INDELs in 39 diagnosis-remission pairs (XLSX 249 kb)

Supplementary Table 7

Protein-altering SNVs and INDELs in 15 candidate genes in (A) diagnosis-only samples and (B) cell lines (XLSX 96 kb)

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De Keersmaecker, K., Atak, Z., Li, N. et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nat Genet 45, 186–190 (2013). https://doi.org/10.1038/ng.2508

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