Abstract

The R98S mutation in ribosomal protein L10 (RPL10 R98S) affects 8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases, and was previously described to impair cellular proliferation. The current study reveals that RPL10 R98S cells accumulate reactive oxygen species which promotes mitochondrial dysfunction and reduced ATP levels, causing the proliferation defect. RPL10 R98S mutant leukemia cells can survive high oxidative stress levels via a specific increase of IRES-mediated translation of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2), mediating BCL-2 protein overexpression. RPL10 R98S selective sensitivity to the clinically available Bcl-2 inhibitor Venetoclax (ABT-199) was supported by suppression of splenomegaly and the absence of human leukemia cells in the blood of T-ALL xenografted mice. These results shed new light on the oncogenic function of ribosomal mutations in cancer, provide a novel mechanism for BCL-2 upregulation in leukemia, and highlight BCL-2 inhibition as a novel therapeutic opportunity in RPL10 R98S defective T-ALL.

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Acknowledgements

We thank the patients who donated samples and the physician assistants, nurse practitioners, and clinicians who acquired the samples. We thank Prof. Adi Kimchi (Weizmann institute of science, Israel) for providing dual-luciferase reporter plasmids.

Author contributions

K.R.K. designed research, performed research, collected data, analyzed data and wrote the paper. S.O.S. conducted the BCL2 IRES-reporter assays and wrote and edited the manuscript. B.V. and S.V. generated the CRISPR-Cas9 Jurkat clones. T.G. and JOdB generated Ba/F3 clones containing human RPL10 WT or R98S, G.R. and S.F. performed and interpreted the 13C6-Glucose tracing experiment. J.V. facilitated the mice studies, and P.S. performed ATP analysis. A.U., A.V.M., C.J.H., J.P.P.M., and J.C. provided the pediatric T-ALL patient data and samples. P.V. and D.C. measured uric acid levels in serum samples. K.D.K. designed research, supervised the study and wrote the paper.

Funding

K.R.K. was supported by the Lady Tata Memorial Trust International Award for research in Leukemia. S.O.S. is recipient of an EMBO long-term postdoctoral fellowship and the EHA José Carreras Junior Research Grant. T.G. was supported by a fellowship “Emmanuel van der Schueren” from Kom op tegen Kanker. B.V. and S.V. are S.B. PhD fellow at FWO (Nos. 1S07118N and 1S49817N). GR is supported by consecutive PhD fellowships from the Emmanuel van der Schueren—Kom op tegen Kanker foundation and FWO. S.M.F. acknowledges funding support from the Concern Foundation (Conquer Cancer Now) and KU-Leuven Methusalem Co-funding. P.V. and D.C. have senior clinical investigator fellowships of the FWO Vlaanderen. This research was funded by an ERC starting grant (No. 334946), FWO funding (G084013N and 1509814N) and a Stichting Tegen Kanker grant (Grant No. 2012-176 and 2016-775) to K.D.K. and by the leukemia research grant 2017 from the “Me To You” foundation to K.R.K.

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Affiliations

  1. Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium

    • Kim R. Kampen
    • , Sergey O. Sulima
    • , Benno Verbelen
    • , Tiziana Girardi
    • , Stijn Vereecke
    • , Jelle Verbeeck
    • , Joyce Op de Beeck
    •  & Kim De Keersmaecker
  2. Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium

    • Gianmarco Rinaldi
    •  & Sarah-Maria Fendt
  3. Department of Oncology, Laboratory of Cellular Metabolism and Metabolic Regulation, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium

    • Gianmarco Rinaldi
    •  & Sarah-Maria Fendt
  4. Department of Pediatric Oncology & Hematology, University Hospitals Leuven, Leuven, Belgium

    • Anne Uyttebroeck
  5. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    • Jules P. P. Meijerink
  6. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom

    • Anthony V. Moorman
    •  & Christine J. Harrison
  7. Department of Gastroenterology-Hepatology and Metabolic Center, University Hospitals Leuven, Leuven, Belgium

    • Pieter Spincemaille
    •  & David Cassiman
  8. Laboratory of Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium

    • Jan Cools
  9. Laboratory of Molecular Biology of Leukemia, Center for Cancer Biology, VIB, Leuven, Belgium

    • Jan Cools
  10. Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium

    • Pieter Vermeersch

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https://doi.org/10.1038/s41375-018-0176-z