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Lookup NU author(s): Claire Schwab, Professor Christine Harrison FRCPath FMedSci
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© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 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.
Author(s): Girardi T, Vereecke S, Sulima SO, Khan Y, Fancello L, Briggs JW, Schwab C, De Beeck JO, Verbeeck J, Royaert J, Geerdens E, Vicente C, Bornschein S, Harrison CJ, Meijerink JP, Cools J, Dinman JD, Kampen KR, De Keersmaecker K
Publication type: Article
Publication status: Published
Journal: Leukemia
Year: 2018
Volume: 32
Issue: 3
Pages: 809-819
Print publication date: 01/03/2018
Online publication date: 24/07/2017
Acceptance date: 04/07/2017
ISSN (print): 0887-6924
ISSN (electronic): 1476-5551
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/leu.2017.225
DOI: 10.1038/leu.2017.225
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