Perfil de expressão gênica da via de deacetilação de histonas mediada por Sirtuinas (SIRTs) na estratificação prognóstica da neoplasia mielodisplásica

Abstract

Sirtuins (SIRTs) are a group of proteins that play a crucial role in various cellular processes, including DNA repair, metabolism, and aging. They have been the subject of significant research interest, particularly in relation to cancer. SIRTs have been implicated in promoting cancer progression by inhibiting cell death pathways and facilitating cancer cell survival. Additionally, some studies have linked increased SIRTs family (SIRT1 to SIRT7) gene expression activity to developing drug resistance in cancer cells, making treatment more challenging. Recently, in a systematic review, our group highlighted the scarcity of studies that establish the role of SIRTs genes in the pathobiology of Myelodysplastic neoplasm (MDS). To assess the gene expression profile of SIRTs (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7) in relation to the pathogenesis and prognostic progression of MDS. This analysis included a cohort of 80 elderly patients diagnosed with MDS and bone marrow samples from 10 healthy individuals. MDS patients were diagnosed based on the World Health Organization (WHO) criteria and stratified according to the prognostic criteria established by the International Prognostic Scoring System-Revised (IPSS-R). We assessed the gene expression levels of SIRTs using the Real-Time PCR Gene Expression (RT-qPCR) method. We observed low expression of SIRT2 (p=0.009), SIRT3 (p=0.048), SIRT4 (p=0.049), SIRT5 (p=0.046), SIRT6 (p=0.043), and SIRT7 (p=0.047) in MDS patients compared to the control group. Additionally, we found increased expression of SIRT4 (p=0.029) in patients aged 60 or above. Furthermore, we identified increased expression of SIRT2 (p=0.016) and SIRT3 (p=0.036) in patients with hemoglobin levels below 8g/dL, increased SIRT4 (p=0.036) in patients with dyserythropoiesis, decreased expression of SIRT2 (p=0.035), SIRT4 (p=0.035), and SIRT7 (p=0.037) in patients with dysgranulopoiesis, increased SIRT1 (p=0.027) in patients with dysmegakaryopoiesis, and increased SIRT4 (p=0.043) in patients with the presence of ring sideroblasts. We also observed high expression of SIRT2 (p=0.045) and SIRT3 (p=0.033) in patients with cytogenetic alterations and increased expression of SIRT2 (p=0.004), SIRT3 (p=0.005), and SIRT4 (p=0.033) in healthy patients compared to those with a normal karyotype. In summary, we identified significantly differential gene expression of SIRTs members in MDS. We identified variations in the expression of SIRTs in cell dysplasias in all 3 cell lines present in BM, as well as variations of SIRTs in patients with very low hemoglobin levels, demonstrating the relationship of these genes with the disease. These defunctions lead to dysplastic and oncogenic characteristics capable of triggering the disease and its prognostic characteristics. Our results revealed significant clinical associations regarding the expression of SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7 genes, demonstrating their potential involvement in the pathogenesis and progression of MDS.