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

Leukemia. 2019 Feb;33(2):319-332. doi: 10.1038/s41375-018-0176-z. Epub 2018 Jun 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Expression Regulation, Leukemic
  • Humans
  • Internal Ribosome Entry Sites*
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mutation*
  • Oxidative Stress / drug effects
  • Phosphorylation
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Protein Biosynthesis*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Ribosomal Protein L10
  • Ribosomal Proteins / genetics*
  • Ribosomal Proteins / metabolism
  • Ribosomes / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Internal Ribosome Entry Sites
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • RPL10 protein, human
  • Ribosomal Proteins
  • Rpl10 protein, mouse