Year: 2025
Type: article
Abstract: ABSTRACT: Metabolic reprogramming is a hallmark of cancer and is essential for sustaining leukemogenesis. In acute myeloid leukemia (AML), a high dependency on oxidative phosphorylation (OXPHOS) is often linked to poor outcomes, and its inhibition has shown to be highly effective. However, most OXPHOS inhibitors are not clinically translatable because of significant side effects. Thus, repurposing safe US Food and Drug Administration-approved drugs that can target OXPHOS is of great interest. Here, we evaluated metformin, an antidiabetic drug that inhibits OXPHOS, in a genetically diverse panel of primary AML samples to identify metabolic profiles that can be used to predict treatment susceptibility. Using label-free quantitative proteome analysis on sorted CD34+/CD117+ AML cells, we performed single-sample gene set enrichment analysis focused on metabolic terms and correlated enrichment scores with metformin sensitivity, followed by functional studies. Ex vivo treatment of AML samples with metformin showed a significant increase in reactive oxygen species levels and ferroptosis induction, especially in samples with disturbed lipid metabolism, such as IDH2- and FLT3-mutant AMLs. In IDH2-mutant cells, cotreatment with palmitate, a saturated fatty acid (FA), increased metformin sensitivity, which could be rescued by CD36 knockdown, rendering these cells more resistant to treatment. Lipidomic analysis revealed profound alterations upon metformin treatment, including increased production of triglycerides and polyunsaturated FAs, further supporting a metabolic shift. We observed upregulation of genes related to lipid droplet formation, including DGAT1, a key enzyme in this process. DGAT1 inhibition was strongly synergistic with metformin, whereas iron chelators acted antagonistically. Our results underscore the potential of leveraging metabolic vulnerabilities in AML to identify more effective and personalized therapeutic strategies.
Source: Blood Advances
Authors: Dominique Sternadt, Diego A. Pereira-Martins, Prodromos Chatzikyriakou, Luise Albuquerque-Simões, Ming Yang, Douglas R. A. Silveira, Albertus T. J. Wierenga, Isabel Weinhäuser, Shanna M. Hogeling, Lieve L. Oudejans, Pilar Casares Alaez, Jean-Emmanuel Sarry, Christian Frezza, Gerwin A. Huls, Lynn Quek, Jan Jacob Schuringa
Institutions: University Medical Center Groningen, University of Groningen, King's College London, Universidade de São Paulo, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne, Centre National de la Recherche Scientifique, Inserm, Centre de Recherches en Cancérologie de Toulouse, La Ligue Contre le Cancer, Université de Toulouse
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W4415749409