Papel do fator de transcrição ikaros na via de sinalização do receptor de célula b em pacientes com leucemia linfocítica crônica.

• Ano de defesa: 2018
• Autor(a) principal: Lacerda, Marcelo Pitombeira de [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Chronic lymphocytic leukemia; Ikaros; B cell receptor; Leucemia linfocítica crônica; Receptor de célula B
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=6549839; https://repositorio.unifesp.br/handle/11600/53130

Introduction: Chronic Lymphocytic Leukemia (CLL) is characterized by the clonal proliferation of mature B-lymphocytes. It is the most common form of leukemia in Western countries, and usually affects older individuals. The B-cell receptor (BCR) is essential for cell proliferation and survival in CLL, and the clinical efficacy of BCR inhibition by Bruton’s tyrosine-kinase (BTK) inhibitors has stressed the relevance of this mechanism in CLL. The Ikaros family of transcription factors is key for the development of B and T lymphocytes, and aberrations in Ikaros have been found in other hematological malignancies. The interaction of Ikaros and BTK, previously described in other scenarios, has not yet been evaluated in CLL. Objectives: To evaluate the expression pattern of genes from the BCR signaling pathway, the protein expression of Ikaros isoforms and BTK, and the interaction between Ikaros and BTK in CLL patients and healthy controls. To correlate these expression patterns with prognostic markers and clinical outcomes in CLL. Methods: Sixty treatment-naïve patients were included, from five hematology centers in São Paulo state. All patients underwent a single blood collection and sample cryopreservation. Results: Median age was 66 years (41-87), and 23 patients were male (38%). At a median follow-up of 23 months (17-30), 10 patients (17%) received treatment, and 4 patients (7%) died. An abnormal expression of BCR signaling pathway genes was observed, with higher BTK and LYN expression and lower SHIP expression, favoring BCR signaling. A higher protein expression of dominant negative (DN) Ikaros isoforms was found, with cytoplasmatic cellular localization of Ikaros and possible loss of interaction with BTK in CLL patients. These findings do not seem to be influenced by known prognostic factors or to impact on clinical outcomes. Conclusions: The predominance of DN Ikaros isoforms is possibly associated with a higher expression of BCR signaling pathway genes, favoring cell proliferation and survival in CLL.