Jurnal Internasional Tidak begitu hilang dalam terjemahan: RPS15 mutasi di CLL
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Landscape mutations of CLL are heterogeneous ranges of repetitive mutations in classical tumor suppressor genes (for example, TP53 ) to mutations in genes involved in splicing machines (for example, SF3B1 ). 2 Recently, 1945. RPS15 mutations were found in low frequencies in newly diagnosed and untreated cohorts, 3 but they affected up to 20% of CLL patients who relapse after chemoimmunotherapy (ie, fludarabine, cyclophosphamide, and rituximab [FCR]). 4 5 In addition, it was noted that about one-third of the 1945 RPS15-raised patients also carried TP53 deviations (i.e., 17p deletion and / or TP53  mutations). 5 6 [1945-1958] Translation of RNA into proteins is a complex and fundamental cellular process, and recent somatic discoveries RPS15 mutations in CLL and mutations in RPL10 RPL5 and RPL11  in acute cell lymphoblastic leukemia 7  have sparked interest in how these mutations may be related to the oncogenesis and progression of disease in hematological malignancies. Some ribosome proteins, including RPS15, have alternative functions suggested besides protein translation in interaction with the MDM2-p53 axis under conditions with nucleolar stress, which then leads to cell cycle arrest. 8 Although the initial functional analysis of mutants RPS15 shows an increase in ubiquitin-mediated p53 degradation, this cannot fully explain the abrogation of this function as a specific oncogenic mechanism. 5 RPS15  mutations in CLL mainly represent heterozygous one single nucleotide variant that occurs almost exclusively within the evolutionary C-terminal region preserved between amino acids 129 and 145, showing strong functional barriers to mutations which occurs in the decoding center of the ribosome. This pattern of mutations shows oncogenic rather than tumor suppressor functions of mutant proteins; However, the exact effects of RPS15 mutations in ribosome function have not been previously described.
Bretones et al investigated the cellular impact of RPS15 mutations. They began by investigating the half-life of RPS15 mutants compared to wild type proteins with stable transcript expressions with 8 different RPS15 mutations, and they detected a half-life decrease in RPS15 mutants, most likely by increased ubiquitination. An important question regarding the effects of the RPS15 mutation is whether or not mutant proteins are incorporated in the ribosome. The authors show that the RPS15 mutant is indeed incorporated in the ribosome and can therefore have an effect on the translational nature of the RPS15  -mutated cells. Furthermore, they assessed the mutant effects of RPS15 on ribosome function and detected an increase in cap-independent translation for 5 mutants, decreased translation fidelity for 2 mutants, and the ability to decrease significantly in detecting stop-codons for 5 mutants (see figure ) Taken together, these features strongly suggest that RPS15 mutations cause changes in ribosome function related to protein synthesis and translation fidelity.
Finally, the authors applied high-throughput protease analysis to describe changes in global proteins for 2 of RPS15 [mutations] most often occur (RPS15 P131S and RPS15 S138F ) compared with RPS15 wild type in nonhematologic cell lines (HEK293T). Proteome profiles replicate with the same mutations converging together, and detailed investigations of altered protein classes indicate that mutant RPS15 P131S causes an increase in the number of proteins associated with DNA replication and extension. In turn, RPS15 S138F causes protein enrichment associated with messenger RNA (mRNA) and processing of peptides. The CLL cell line often proves challenging in functional studies, and studies that replicate in the CLL MEC-1 cell line do not reveal specific mutant protease profiles. However, the comparison of all mutants with wild type profiles reveals a pattern similar to that in the HEK293T experiment. This profile also involves a decrease in regulation of pathways which can lead to metabolic reprogramming of aerobic glycolysis, which is in line with the Warburg effect described earlier.
Overall, this study shows that RPS15  mutations, especially occurring at the center decoding ribosomes, causing reduced RPS15 levels and changing ribosomal efficiency which in turn causes global proteom changes. Based on data from different ribosomopathies, the authors speculate that ribosome mutations can produce changes from hypo- to hyperproliferative phenotypes. Initially, the stress of the ribosome can choose mutations that pass through the quality control of the ribosome, thereby increasing the number of damaged ribosomes. Conversely, mutated ribosomes can cause changing patterns of protein expression, which can contribute to the transformation and development of leukemia. Although the data presented here are based primarily on experiments carried out in cell lines, it is important to further investigate whether RPS15  mutations cause similar differences in ribosome efficiency and protein synthesis in primary CLL cells too, especially exploring the effects in vivo (i.e., in the context of the tumor microenvironment). For this purpose, detailed analysis of the main pathways and processes that are affected by the translation of disturbed mRNAs and their downstream effects will be needed to determine the effect of causes of ribosome mutations on CLL pathobiology. As shown in the article by Bretones et al and by others, 3 19 –  5 RPS15 mutations are mainly enriched in patients with aggressive diseases who have a tendency to relapse higher after treatment with chemotherapy-chemotherapy. In particular, the authors observed increased resistance to fludarabine, and to a lesser extent the B cell receptor-signal receptors, at least for cells carrying RPS15 mutations . Therefore, it is important to study potential additional treatment or combination therapy targets for this group of poor prognostic CLL patients.
- Submitted September 24 2018.
- Received September 27 2018.
- © 2018 by The American Society of Hematology