Investigation of mitochondrial metabolism in the biology of myelodysplastic syndrome.

• Grant number: 23/14338-5
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2024
• End date: January 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fabíola Traina
• Grantee: Fabíola Traina
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Myelodysplastic syndrome (MDS) is a heterogeneous group of hematological neoplasms characterized by ineffective hematopoiesis, cytopenias and risk of progression to acute myeloid leukemia and which mainly affects the elderly population. Mitochondrial dysfunction and stem cell exhaustion are two hallmarks of aging commonly found in MDS. Clonal hematopoiesis is perpetuated by inflammation and is involved in the development and progression of MDS. Recently, it was identified that metformin suppressed the growth of cells with clonal hematopoiesis. However, the contribution of mitochondrial metabolism to the pathophysiology, cell survival and management of patients with MDS has not yet been investigated. The objectives of the research will be to investigate and compare mitochondrial metabolism, the inflammatory and protein profile, and the presence of mutations in genes related to clonal hematopoiesis, and finally, to evaluate the effect of mitochondrial complex inhibitors on the clonogenicity of myelodysplastic cells. Bone marrow cells from patients with MDS will be subjected to exome analysis to investigate mutations in genes related to clonal hematopoiesis and myeloid neoplasms, immunoassay to evaluate inflammatory cytokines, evaluation of mitochondrial metabolism in total bone marrow cells and in different compartments of hematopoiesis: tumor microenvironment, innate and adaptive immune microenvironment. The effects of ex vivo treatment with electron transport chain barrier complex inhibitors on myelodysplastic cells will be evaluated using a clonogenic assay. Bioinformatics analyzes for the omics data and statistical analyzes will be performed as appropriate. (AU)