Alterations in the miRNA profile and its impact on the survival of B-1 cells and their precursors during aging

• Grant number: 21/05377-1
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2021 - October 31, 2023
• Field of knowledge: Biological Sciences - 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: Janete Maria Cerutti ; Rodrigo Pinheiro Araldi

Abstract

miRNA deregulation appears in neoplastic conditions, including hematological diseases. Decreased levels of miR-15a/16 are shown in the human Chronic Lymphocytic Leukemia (CLL) and also in disease-murine models, where both present apoptosis-resistant cells with increase in BCL-2 expression, an anti-apoptotic molecule regulated by miR-15a/16. In CLL, failures in apoptosis system correlates with higher hyperproliferative ratio of cells with phenotype similar to B-1 cells, which accumulates in lymphoid organs, bone marrow and peripheral blood. Another CLL characteristics are alterations in zinc-finger transcription factor Ikaros and symptom manifestations beginning after 50 years in humans. It was shown that CLL patients present non-functional localization of Ikaros as well as the increase of its negative isoforms. Contributing to that, Ikaros silencing in B-1 cells resulted in higher proliferation and resistance to apoptosis entrance. Hence, Ikaros absence could impact proliferation and apoptosis control, probably by its interaction with miRNAs. Immune system aging affects production and function of T and B lymphocytes. Senescence implies in the higher susceptibility to infection but also implies in predisposition to hyperproliferative diseases, such as autoimmunity and leukemias. It is known that B-1 and B-1 cell progenitors accumulate in aged mice, but the cause for that is unrevealed. Our group showed that in 30-week middle-aged mice, B-1 cell progenitors present altered miRNA profile related to apoptosis control. However, the molecular mechanism to that and the possible implication of B-1 cell progenitor in leukemia establishment is not uet clear. Based on this, the current proposal aims to analyze Ikaros participation in miRNAs control, specially miRNAs related to apoptosis system. Our hypothesis is that deregulation in Ikaros complex results in higher HDACs activity, leading to decrease in miR-15a/16 expression and consequent deregulated proliferation and defects in cell death entrance. Also, the miRNA profile of B-1 cells and their progenitors along aging will be analyzed to search for immunosenescence impact in susceptibility to hyperproliferation. Hence, this project search for results that put in evidence loss of Ikaros and aging as key mechanisms to predisposition to cell survival and hyperproliferation, processes controlled by miRNAs. (AU)