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Blood. 2018 Nov 29;132(22):2375-2388. doi: 10.1182/blood-2017-09-804401. Epub 2018 Sep 4.

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

Author information

1
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
2
Lymphoid Neoplasm Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
3
Department of Cell Biology, Harvard Medical School, Boston, MA.
4
Hematology and Pathology Department, Hospital Clínic, Barcelona, Spain.
5
Centro de Investigación en Red de Cáncer, Madrid, Spain; and.
6
Departament d'Anatomia Patològica, Universitat de Barcelona, Barcelona, Spain.

Abstract

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 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 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.

PMID:
30181176
PMCID:
PMC6410914
[Available on 2019-11-29]
DOI:
10.1182/blood-2017-09-804401

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