2. Academic Validation
  3. High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability

High mtDNA content identifies oxidative phosphorylation-driven acute myeloid leukemias and represents a therapeutic vulnerability

  • Signal Transduct Target Ther. 2025 Jul 14;10(1):222. doi: 10.1038/s41392-025-02303-x.
Diego A Pereira-Martins 1 2 3 4 5,  Isabel Weinhäuser 2 3 4 5,  Emmanuel Griessinger 2,  Juan L Coelho-Silva 1 3 4,  Douglas R Silveira 5,  Dominique Sternadt 2,  Ayşegül Erdem 2 6,  Bruno Kosa L Duarte 7,  Prodromos Chatzikyriakou 5,  Lynn Quek 5,  Antonio Bruno Alves-Silva 3 4,  Fabiola Traina 3 4,  Sara T Olalla Saad 7,  Jacobien R Hilberink 2,  Amanda Moreira-Aguiar 1,  Maria L Salustiano-Bandeira 1 8,  Marinus M Lima 1,  Pedro L Franca-Neto 1,  Marcos A Bezerra 1,  Nisha K van der Meer 2,  Emanuele Ammatuna 2,  Eduardo M Rego 3 4 8,  Gerwin Huls 2,  Jan Jacob Schuringa 9,  Antonio R Lucena-Araujo 10
Affiliations

Affiliations

  • 1 Department of Genetics, Federal University of Pernambuco, Recife, Brazil.
  • 2 Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
  • 3 Department of Medical Imaging, Haematology, and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
  • 4 Center for Cell Based Therapy, São Paulo Research Foundation, Ribeirão Preto, SP, Brazil.
  • 5 Myeloid Leukaemia Genomics and Biology Group, School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
  • 6 Cellular Metabolism and Microenvironment Laboratory, de Duve Institute, UCLouvain, Brussels, Belgium.
  • 7 Hematology and Transfusion Medicine Center, University of Campinas, Campinas, Brazil.
  • 8 Hematology Division, LIM31, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil.
  • 9 Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. j.j.schuringa@umcg.nl.
  • 10 Department of Genetics, Federal University of Pernambuco, Recife, Brazil. antonio.araujo@ufpe.br.
PMID: 40653487 DOI: 10.1038/s41392-025-02303-x
Abstract

Metabolic reprogramming is a hallmark of Cancer, with acute myeloid leukemia (AML) being no exception. Mitochondrial function, particularly its role in protecting tumor cells against chemotherapy, is of significant interest in AML chemoresistance. In this study, we identified mitochondrial DNA content (mtDNAc), measured by quantitative PCR, as a simple and precise marker to stratify the metabolic states of AML patients. We show that patients with high mtDNAc are associated with increased Mitochondrial Metabolism and a higher dependency on Oxidative Phosphorylation (OXPHOS), often correlating with chemoresistance. Clinically, patients receiving cytarabine and an anthracycline-based regimen (7 + 3 regimen) experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence. Ex vivo experiments using primary AML samples confirmed cytarabine resistance in high mtDNAc patients, which could be overcome by inhibiting mitochondrial complex I. The FDA-approved drug metformin, which targets Mitochondrial Metabolism, significantly enhanced Apoptosis in response to chemotherapy or targeted agents, such as venetoclax, in AML models. However, metformin-treated cells adapted by increasing glycolysis and NAD+ production, a resistance mechanism that could be bypassed by targeting the nicotinamide phosphoribosyltransferase (NAMPT) enzyme. In summary, we demonstrated that mtDNAc is an effective tool for assessing the metabolic state of AML cells. This method can be easily implemented in clinical practice to identify chemoresistant patients and guide personalized treatment strategies, including novel combination therapies for those with a high reliance on Mitochondrial Metabolism.

Figures
Products