How the RPL10 R98S mutation translates T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a genetically complex and aggressive hematologic cancer caused by accumulation of somatic mutations in developing T-cells. In order to better understand the genetic defects present in T-ALL, we performed whole exome sequencing on 67 T-ALL samples. The most significant new finding of this study was the identification of somatically acquired mutations in the ribosomal protein L5 (RPL5) and L10 (RPL10) genes in about 10% of pediatric patients. RPL5 and RPL10 encode essential proteins of the 60S ribosomal subunit. Mutations in several ribosomal proteins have been described in a series of inherited disorders, known as ribosomopathies, that result in hematopoietic defects and a predisposition to develop leukemia and solid tumors. Our findings provided however the first genetic evidence directly linking ribosomes to cancer. A series of additional somatic ribosome defects have recently been discovered in cancer, yet their underlying oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent arginine to serine mutation at position 98 (R98S) in RPL10, found in 7.9% of pediatric T-ALL patients. We show that engineered mouse lymphoid cells as well as T-ALL xenografts samples expressing RPL10-R98S display elevated expression of components of the oncogenic JAK-STAT signaling pathway. Of biological relevance, these cells also display enhanced Jak-Stat pathway activation upon cytokine stimulation and increased sensitivity to JAK-STAT inhibitors. Interestingly, RPL10-R98S positive leukemia patients showed a nearly mutually exclusive mutation pattern between RPL10-R98S and JAK-STAT lesions, suggesting that RPL10-R98S also modulates this cascade in human T-ALL. Mechanistically, besides transcriptional changes, we observed reduced proteasome activity, reduced degradation of Jak1, and enhanced sensitivity to clinically used proteasome inhibitors in RPL10-R98S expressing cells. Additionally, we observed RPL10-R98S associated reduction of apparent programmed ribosomal frameshifting, an emerging mechanism to regulate the expression of cytokine receptors, at several identified ribosomal frameshift signals in mouse and human JAK-STAT genes. We thus highlight modulation of the oncogenic JAK-STAT cascade as a novel cancer-promoting activity of a ribosomal mutation.

Publication year:2017

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