Expressão de alvos da via ubiquitina-proteassoma (UBE2T, UBE2O, USP7 E USP15) na estratificação prognóstica de pacientes com síndrome mielodisplásica

Abstract

Myelodysplastic Syndrome (MDS) comprises a group of clonal hematological disorders closely associated with the presence of genomic instability in hematopoietic progenitor stem cells, commonly characterized by the presence of chromosomal alterations and an increased risk of progression to Acute Myeloid Leukemia (AML). The ubiquitin-proteasome system is an important proteolytic system with a role in the regulation of various cellular functions, such as intracellular protein breakdown, cell cycle control, apoptosis and DNA repair. The role of ubiquitination (UBE2T and UBE2O) and deubiquitination (USP7 and USP15) genes in the pathophysiology of MDS is unknown. In this context, we sought, in this study, to evaluate the expression profile of the UBE2T, UBE2O, USP7 and USP15 genes in relation to the pathogenesis and clinical-laboratory and prognostic stratification of the Myelodysplastic Syndrome. Initially, an in silico Pan-Cancer evaluation was performed using the Gene Expression Profling Interactive Analysis (GEPIA) database to predict the differential expression profile of the UBE2T, UBE2O, USP7 and USP15 genes, as well as their role in the survival of the patients. patients diagnosed with onco-hematological diseases, with a focus on MDS. Subsequently, we validated these findings in a cohort of 72 Brazilian patients with MDS and 4 control subjects in order to investigate the role of the expression of these genes in the pathogenesis and prognostic stratification of MDS. The research was submitted and approved by the Ethics Committee for Research with Human Beings (PROPESQ-UFC - nº 35871620.9.0000.5054 / HGF/SUS - nº 35871620.9.3001.5040). As a result, from Pan-Cancer screening in 30 different types of cancers in the GEPIA database, we identified the differential expression profile of the UBE2T, UBE2O, USP7 and USP15 genes only in one type of onco-hematological disease, AML, data on the expression of these genes in GEPIA for MDS were not identified. In AML, it was identified that the UBE2T gene had a reduced expression in patients with the disease compared to controls. No differences were identified regarding the expression of these genes and survival in patients with AML. In evaluating the expression of these genes in MDS in Brazilian patients, we identified that only the USP15 gene had reduced expression compared to healthy individuals (p=0.03). Regarding the clinical and laboratory variables of MDS, an increase in the expression of the UBE2T gene was identified in patients with chromosomal abnormalities compared to patients with normal karyotype (p=0.0321). The USP7 and USP15 genes were positive and strongly correlated (r=0.82; r2=0.67; p<0.0001), reinforcing the participation of these genes in the same pathway in MDS. Our results highlight that the differential gene expression of the USP15-USP7 and UBE2T axis may play an important role in the control of genomic instability, establishing one of the most striking features in MDS, chromosomal abnormalities.