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The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL

Lookup NU author(s): Professor Anthony Moorman, Professor Christine Harrison FRCPath FMedSci

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Abstract

© 2018 Macmillan Publishers Limited, part of Springer Nature 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.


Publication metadata

Author(s): Kampen KR, Sulima SO, Verbelen B, Girardi T, Vereecke S, Rinaldi G, Verbeeck J, Op de Beeck J, Uyttebroeck A, Meijerink JPP, Moorman AV, Harrison CJ, Spincemaille P, Cools J, Cassiman D, Fendt S-M, Vermeersch P, de Keersmaecker K

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2018

Volume: 33

Issue: 2

Pages: 319-322

Print publication date: 01/02/2019

Online publication date: 21/06/2018

Acceptance date: 21/05/2018

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Nature Publishing Group

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

DOI: 10.1038/s41375-018-0176-z


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