Estudo do papel dos genes SALL4 e CHFR em síndrome mielodisplásica primária e sua correlação com as características morfológicas, citogenéticas e clínicas

• Autor(a) principal: Alvarenga, Tatiana Fonseca
• Data de Publicação: 2022
• Outros Autores: [e-mail]
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/20345
• topic: Primary Myelodysplastic Syndrome; Cytogenetic; Dysplasias; SALL4; CHFR; Diagnostic and prognostic biomarkers; Síndrome Mielodisplásica Primária; Alterações citogenéticas; Displasias; SALL4; CHFR; Biomarcadores de diagnóstico e prognóstico; Medula óssea – Doenças; Análise Citogenética; CIENCIAS DA SAUDE::MEDICINA

Introduction and objective: Primary myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic stem cell diseases, characterized by ineffective hematopoiesis, increased intramedullary apoptosis, bone marrow dysplasias and peripheral blood cytopenias. Morphological characteristics and specific chromosomal alterations have reflected different biological issues. The natural history of MDS is highly variable, and may present with early forms of the disease with high survival or more advanced forms that can rapidly progress to acute myeloid leukemia (AML). The objective of this work was to study the associations of morphological, cytogenetic and molecular findings with the clinical characteristics of patients to characterize the role of SALL4 and CHFR genes in the development of MDS and its evolution to AML. Methodology: Morphological analysis was performed on bone marrow biopsies and myelogram. Cytogenetic analysis was performed on bone marrow cells using the GTG banding technique and fluorescence in situ hybridization (FISH). The expression pattern of SALL4 and CHFR genes was analyzed by quantitative real-time PCR and by immunohistochemical study. Statistical analysis was considered significant when p<0,05. Results: Patients were classified according to the WHO in early stages: MDS-SLD (25 patients), MDS-MLD (44 patients), MDS-RS (2 patients); advanced stages: MDS-EB-1 (14 patients), MDS-EB-2 (12 patients) and AML secondary to MDS (3 patients). Chromosomal abnormalities were detected in 39 patients (39%). The most frequent abnormalities were: complex karyotypes, +8, -7/del(7q), del(11q) and del(17p)/i(17q). Patients with advanced disease had a higher incidence of hypercellular bone marrow (p<0,006), increased myeloid:erythroid ratio (p<0,001), medullary architectural loss (p<0,001), megakaryocytes with nuclear hypolobulation (p<0,011) and of ALIP (p<0,001). Regarding progression to leukemia, those with a worse prognosis by the IPSS and IPSS-R had a higher risk of transformation to AML (p<0.001). Chromosomal abnormalities were detected in all patients with SALL4 expression. These patients had advanced disease. Patients with higher SALL4 expression had lower survival (p<0.0014). All patients with increased expression of SALL4 had leukemic evolution (p<0.02). Abnormal karyotypes and intermediate and unfavorable cytogenetic risk groups by IPSS and IPSS-R were associated with lower CHFR expression levels, suggesting an association with the presence of aneuploidies. Conclusion: Bone marrow biopsy is an auxiliary method in the diagnosis of MDS and has prognostic value, as well as the cytogenetic study. Our results suggest that high expression of SALL4 and low expression of CHFR play an important role in the development of MDS and its evolution to AML, being associated with unfavorable prognosis, and they are potential biomarkers of disease evolution