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Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia.

ABSTRACT

Genomic studies have recently identified as a new driver gene in aggressive and chemorefractory cases of chronic lymphocytic leukemia (CLL). encodes a ribosomal protein whose conserved C-terminal domain extends into the decoding center of the ribosome. We demonstrate that mutations in highly conserved residues of this domain affect both protein stability -by increasing its ubiquitin-mediated degradation- and cell proliferation rates. On the other hand, we show that mutated RPS15 can be loaded into the ribosomes, directly impacting on global protein synthesis and/or translational fidelity in a mutation-specific manner. Quantitative mass-spectrometry analyses suggest that variants may induce additional alterations in the translational machinery as well as a metabolic shift at the proteome level in both HEK293T and MEC-1 cells. These results indicate that CLL-related RPS15 mutations might act following patterns known for other ribosomal diseases, likely switching from a hypo- to a hyperproliferative phenotype driven by mutated ribosomes. In this scenario, loss of translational fidelity causing altered cell proteostasis can be proposed as a new molecular mechanism involved in CLL pathobiology. Copyright © 2018 American Society of Hematology.