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

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.

SUBMITTER: Kampen KR

PROVIDER: S-EPMC6169730 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Kampen Kim R KR Sulima Sergey O SO Verbelen Benno B Girardi Tiziana T Vereecke Stijn S Rinaldi Gianmarco G Verbeeck Jelle J Op de Beeck Joyce J Uyttebroeck Anne A Meijerink Jules P P JPP Moorman Anthony V AV Harrison Christine J CJ Spincemaille Pieter P Cools Jan J Cassiman David D Fendt Sarah-Maria SM Vermeersch Pieter P De Keersmaecker Kim K

Leukemia 20180621 2

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 translati ...[more]

PMID: 29930300

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Project description:Internal ribosome entry site (IRES)-driven translation is a common strategy among positive-sense, single-stranded RNA viruses for bypassing the host cell requirement of a 5' cap structure. In the current study, we identified the ribosomal protein L13 (RPL13) as a critical regulator of IRES-driven translation of foot-and-mouth disease virus (FMDV) but found that it is not essential for cellular global translation. RPL13 is also a determinant for translation and infection of Seneca Valley virus (SVV) and classical swine fever virus (CSFV), and this suggests that its function may also be conserved in unrelated IRES-containing viruses. We further showed that depletion of DEAD box helicase DDX3 disrupts binding of RPL13 to the FMDV IRES, whereas the reduction in RPL13 expression impairs the ability of DDX3 to promote IRES-driven translation directly. DDX3 cooperates with RPL13 to support the assembly of 80S ribosomes for optimal translation initiation of viral mRNA. Finally, we demonstrated that DDX3 affects the recruitment of the eukaryotic initiation factor eIF3 subunits e and j to the viral IRES. This work provides the first connection between DDX3 and eIF3e/j and recognition of the role of RPL13 in modulating viral IRES-dependent translation. This previously uncharacterized process may be involved in selective mRNA translation.IMPORTANCE Accumulating evidence has unveiled the roles of ribosomal proteins (RPs) belonging to the large 60S subunit in regulating selective translation of specific mRNAs. The translation speciﬁcity of the large-subunit RPs in this process is thought provoking, given the role they play canonically in catalyzing peptide bond formation. Here, we have identified the ribosomal protein L13 (RPL13) as a critical regulator of IRES-driven translation during FMDV infection. Our study supports a model whereby the FMDV IRESs recruit helicase DDX3 recognizing RPL13 to facilitate IRES-driven translation, with the assistance of eIF3e and eIF3j. A better understanding of these specific interactions surrounding IRES-mediated translation initiation could have important implications for the selective translation of viral mRNA and thus for the development of effective prevention of viral infection.

Dataset Information

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

Publications

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

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