Modeling and epigenetic alterations in immune aplastic anemia

• Grant number: 24/20028-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2025
• End date: March 31, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Laisa Yasmin de Souza
• Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP)
• Associated research grant: 13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID

Abstract

Bone marrow failure is a severe hematologic disease characterized by dysfunction in blood cell production due to the inability of the bone marrow to sustain hematopoiesis. Clinically, it presents as cytopenia, affecting the three major cell lineages: red blood cells, white blood cells, and platelets. Among the forms of bone marrow failure, immune aplastic anemia (AA) stands out as an acquired condition involving an immune attack on the bone marrow, leading to peripheral pancytopenia. Immune AA is triggered by environmental factors such as exposure to chemicals, viral infections, and potential endogenous antigens generated by genetically altered cells. Standard treatment includes allogeneic hematopoietic stem cell transplantation (HSCT) or intensive immunosuppressive therapies (IST) with antithymocyte globulin and cyclosporine, often combined with eltrombopag. Despite initial success in many cases, disease relapse is common, suggesting that intrinsic defects in hematopoietic stem and progenitor cells (HSPCs) and the prolonged impact of immune attacks may impair their function. Epigenetics, particularly alterations induced by the immune environment, may emerge as a factor in modulating HSPC function, negatively influencing cell proliferation and differentiation even after the cessation of immune-mediated attacks. This study proposes to investigate the epigenetic signatures induced by immune-mediated attacks on HSPCs from patients with AA, aiming to understand how these epigenetic changes impact hematopoiesis and contribute to the persistence of the disease even after immunosuppressive therapies. The study will analyze 18 patients with immune aplastic anemia (AA), including six in partial remission, six in complete remission, and six healthy controls. Hematopoietic stem cells (HSPCs) will be isolated from bone marrow samples from participants and subjected to DNA methylation analysis, gene expression by RNA-seq, and proteomics by LC-MS/MS. In addition, chromatin accessibility will be assessed via ATAC-seq. The data obtained will be analyzed using a combination of bioinformatics tools and statistical methods to validate the significance of observed differences, applying appropriate statistical tests for each dataset. (AU)