Exploiting mitochondrial genome expression as a therapeutic vulnerability in acute myeloid leukemia

• Grant number: 24/21624-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2025
• End date: May 31, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: João Agostinho Machado Neto
• Grantee: Juan Luiz Coelho da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Acute myeloid leukemia (AML) is characterized by the clonal expansion of immature myeloid cells, resulting in hematopoietic failure, with symptoms such as anemia and infections. Clinical outcomes are unfavorable, with an estimated overall survival inferior to 25% in five years. AML cells exhibit metabolic reprogramming that promotes dependence on oxidative phosphorylation for ATP production. Research from our group has shown that high levels of mitochondrial DNA, observed in AML patients, are associated with chemotherapy resistance, resulting in poorer clinical outcomes. Additionally, mitochondrial metabolic adaptation, as demonstrated by increased mitochondrial mass and respiratory capacity, is also linked to chemoresistance, particularly in leukemic stem cells. Pharmacological interventions targeting mitochondrial metabolism have shown potential to enhance the efficacy of available treatments, suggesting that regulating mitochondrial genome expression may be a promising therapeutic strategy for AML. To this end, we will select selective inhibitors and repurposed compounds that act on regulators of mitochondrial genome expression and determine their cytotoxic effects in AML cell models. The most promising inhibitors will be evaluated for their impact on mitochondrial dynamics and metabolic function using Seahorse analysis. Molecular consequences will be assessed by label-free global proteomics. Finally, the efficacy of the treatments will be determined in AML xenograft murine models.