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

Gabriel Bretones, Miguel G. Álvarez, Javier R. Arango, David Rodríguez, Ferran Nadeu, Miguel A. Prado, Rafael Valdés-Mas, Diana A. Puente, Joao A. Paulo, Julio Delgado, Neus Villamor, Armando López-Guillermo, Daniel J. Finley, Steven P. Gygi, Elías Campo, Víctor Quesada and Carlos López-Otín

Key points

  • RPS15 alterations in CLL induce mutation-dependent changes in global protein synthesis and translational fidelity.

  • RPS15 mutations disrupt cellular proteostasis through proteomic changes mainly affecting mRNA translation as well as cell metabolism.


Genomic studies have recently identified RPS15 as a new driver gene in aggressive and chemorefractory cases of chronic lymphocytic leukemia (CLL). RPS15 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 RPS15 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.

  • Submitted September 29, 2017.
  • Accepted August 24, 2018.