Mapping of miRNA alterations during B-1 cell leukemogenesis

• Grant number: 24/18354-8
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2025
• End date: May 31, 2028
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Ana Flavia Popi
• Grantee: Ana Flavia Popi
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Alexandre de Castro Keller ; Celso Arrais Rodrigues da Silva ; Eduardo Magalhães Rego ; Rodrigo Nalio Ramos

Abstract

Chronic Lymphocytic Leukemia (CLL) is the most common form of hematological cancer in adults, particularly in individuals over the age of 50. CLL is characterized by the accumulation of clonal B lymphocytes that are resistant to apoptosis and exhibit a phenotype similar to B-1 cells. Studies show that resistance to apoptosis in CLL cells is associated with defective regulation of anti-apoptotic proteins, such as Bcl-2, which are controlled by miRNAs.miRNAs are small non-coding RNAs that play a crucial role in the post-transcriptional regulation of genes involved in various cellular processes, including cell proliferation and death. The dysregulation of miRNAs has been extensively studied in various types of cancer, and their role as oncogenes or tumor suppressor genes is well established. For example, the miR-15a/16 cluster is known to negatively regulate the expression of Bcl-2, a key protein in the intrinsic apoptosis pathway. Reduced levels of miR-15a/16 result in the overexpression of Bcl-2, contributing to the resistance to apoptosis observed in CLL cells.Additionally, the expression of Ikaros, a transcription factor essential for B lymphocyte development, is also dysregulated in CLL. Ikaros functions in complexes with histone deacetylases (HDACs) to regulate gene expression, and its silencing has been associated with increased proliferation of B-1 cells and resistance to apoptosis, characteristics observed in CLL. Therefore, the interaction between Ikaros and miRNAs, such as miR-15a/16, may be a critical mechanism contributing to the pathogenesis of CLL during aging.Several elements still need to be evaluated to fully understand the molecular alterations that lead to the emergence of leukemic cells, aiming to comprehend the process of cellular transformation, while primarily providing data that may contribute to more targeted therapeutic approaches. Given this scenario, it is essential to investigate how miRNA regulation and Ikaros function interact to influence B-1 cell survival. In this proposal, we intend to monitor the molecular changes that accumulate during the leukemogenesis process. The approach will involve inducing the most frequent molecular alterations in CLL and monitoring the emergence of different stages of CLL. This research may provide new insights into the molecular mechanisms leading to leukemogenesis, as well as identify potential therapeutic targets that can be used for the diagnosis, prevention, or treatment of CLL. (AU)