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.

The Physiopathology of T- Cell Acute Lymphoblastic Leukemia: Focus on Molecular Aspects

“…Ribosomal genes RPL5 (1p22), RPL10 (Xq28), and RPL11 (1p36) have been described to be mutated in T-ALL (32). RPL10 mutations are found in 6-8% of pediatrics, with the recurrent RPL10 R98S mutant allele in most cases (32,88). RPL10 R98S mutant leukemia cells may increase the expression of antiapoptotic protein BCL2.…”

“…RPL10 R98S mutant leukemia cells may increase the expression of antiapoptotic protein BCL2. RPL10 R98S mutations are mutually exclusive with JAK/STAT mutations and are associated with a hypoproliferative phenotype (88).…”

“…In addition, imatinib, dasatinib, and nilotinib are all active against NUP214-ABL1-positive T-cells, with different ability to inhibit this kinase and induce apoptosis in preclinical studies (102). Finally, RPL10 R98S mutant leukemia cells are potentially sensitive to Bcl2 inhibitor venetoclax (88). Venetoclax combined to chemotherapy induced a morphological remission in 60% of patients (including ETP-ALL) in a recent retrospective study (103).…”

Loss of m1acp3Ψ ribosomal RNA modification is a major feature of cancer

“…Thus, the hypo-m 1 acp 3 Ψ), a mo phenotype may demarcate a class of 'onco-ribosome' with deregulated translation. It is noteworthy that the two largest effect size RP cancer driver mutations also occur at the ribosomal P-site/tRNA interface, the RPL10 p.R98S at the peptidyl transfer site 17,18 and RPS15 C` tail mutations adjacent (<12Å) to 1248.m 1 acp 3 Ψ), a mo ( Fig. 2a) suggesting that the ribosomal P-site is a convergent multi-cancer oncogenic hot-spot.…”

“…It has been hypothesized that cancer cells contain a functionally specialized class of ribosomes to facilitate rapid protein synthesis, termed the "onco-ribosomes" 15,16 . Cancer genomics has supported this notion with the identification of several oncogenic driver mutations in RP genes 14 , the best characterized of which are RPL10 (uL16) p.R98S in T-cell acute lymphoblastic leukemia 17,18 and RPS15 (uS19) C' terminal mutations in chronic lymphocytic leukemia 19 . In addition, germline mutations such as in DBA patients and in RPS20 can cause heredity cancers including colorectal carcinoma (CRC) 20,21 .…”