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Transcriptional control and signal transduction, cell cycle

The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling

Leukemia volume 32, pages 809–819 (2018)Cite this article

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Abstract

Several somatic ribosome defects have recently been discovered in cancer, yet their oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent R98S mutation in ribosomal protein L10 (RPL10 R98S) found in T-cell acute lymphoblastic leukemia (T-ALL). The JAK-STAT signaling pathway is a critical controller of cellular proliferation and survival. A proteome screen revealed overexpression of several Jak-Stat signaling proteins in engineered RPL10 R98S mouse lymphoid cells, which we confirmed in hematopoietic cells from transgenic Rpl10 R98S mice and T-ALL xenograft samples. RPL10 R98S expressing cells displayed JAK-STAT pathway hyper-activation upon cytokine stimulation, as well as increased sensitivity to clinically used JAK-STAT inhibitors like pimozide. A mutually exclusive mutation pattern between RPL10 R98S and JAK-STAT mutations in T-ALL patients further suggests that RPL10 R98S functionally mimics JAK-STAT activation. Mechanistically, besides transcriptional changes, RPL10 R98S caused reduction of apparent programmed ribosomal frameshifting at several ribosomal frameshift signals in mouse and human Jak-Stat genes, as well as decreased Jak1 degradation. Of further medical interest, RPL10 R98S cells showed reduced proteasome activity and enhanced sensitivity to clinical proteasome inhibitors. Collectively, we describe modulation of the JAK-STAT cascade as a novel cancer-promoting activity of a ribosomal mutation, and expand the relevance of this cascade in leukemia.

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Acknowledgements

We thank the EPFL proteomics core facility and the VIB Nucleomics core facility for their excellent support on mass spectrometry and RNA sequencing respectively. We thank Somersault1824 for preparing Figure 7. TG is funded by the fellowship ‘Emmanuel van der Schueren’ Kom op tegen kanker. SOS was supported by a long-term EMBO Fellowship (ALTF 1263-2014), the European Commission and Marie Curie Actions (LTFCOFUND2013, GA-2013-609409) and by a José Carreras EHA junior research grant. SV is SB PhD fellow at FWO (n° 1S49817N). KRK is supported by the Lady Tata Memorial Trust International Award for research in Leukaemia. This research was funded by an ERC starting grant (n° 334946), FWO funding (G067015N, G084013N and 1509814N) and a Stichting Tegen Kanker grant (grant n° 2012-176) to KDK. This work was partially supported by funding to JDD by the National Institutes of Health (R01HL119439 and R01GM117177).

Author contributions

TG, JDD and KDK designed the research. TG, SV, SOS, KRK and SB developed methodology. TG, SV, SOS, KRK, YK, EG, JWB, JODB, JV and JR performed the research. TG, SV, SOS, KRK, YK, LF, CV and KDK analyzed the data. JPM, CS, EG, CJH and JC provided administrative, technical and material support. TG, SV, SOS, LF, CJH, JPM, JC, JDD and KDK wrote and edited the paper. JDD and KDK supervised the study.

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Author notes

  1. T Girardi, S Vereecke and S O Sulima: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, KU Leuven—University of Leuven, LKI—Leuven Cancer Institute, Leuven, Belgium

    T Girardi, S Vereecke, S O Sulima, L Fancello, J Op de Beeck, J Verbeeck, J Royaert, K R Kampen & K De Keersmaecker

  2. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA

    Y Khan, J W Briggs & J D Dinman

  3. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research Newcastle University, Newcastle-upon-Tyne, UK

    C Schwab & C J Harrison

  4. VIB Center for Cancer Biology, Leuven, Belgium

    E Geerdens, C Vicente, S Bornschein & J Cools

  5. KU Leuven—University of Leuven, Center for Human Genetics, LKI—Leuven Cancer Institute, Leuven, Belgium

    E Geerdens, C Vicente, S Bornschein & J Cools

  6. Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands

    J P Meijerink

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Correspondence to K De Keersmaecker.

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Girardi, T., Vereecke, S., Sulima, S. et al. The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling. Leukemia 32, 809–819 (2018). https://doi.org/10.1038/leu.2017.225

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