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

Kim R. Kampen, Sergey O. Sulima, Benno Verbelen, Tiziana Girardi, Stijn Vereecke, Gianmarco Rinaldi, Jelle Verbeeck, Joyce Op de Beeck, Anne Uyttebroeck, Jules P.P. Meijerink, Anthony V. Moorman, Christine J. Harrison, Pieter Spincemaille, Jan Cools, David Cassiman, Sarah Maria Fendt, Pieter Vermeersch, Kim De Keersmaecker

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)319-332
Number of pages14
JournalLeukemia
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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