Riboflavin drives nucleotide biosynthesis and iron-sulfur metabolism to promote acute myeloid leukemia
Year: 2025
Type: preprint
Abstract: Riboflavin is a diet-derived vitamin in higher organisms that serves as a precursor for flavin mononucleotide and flavin adenine dinucleotide, key cofactors that participate in oxidoreductase reactions. Here, using proteomic, metabolomic and functional genomics approaches, we describe a specific riboflavin dependency in acute myeloid leukemia and demonstrate that, in addition to energy production via oxidative phosphorylation, a key biological role of riboflavin is to enable nucleotide biosynthesis and iron-sulfur cluster metabolism. Genetic perturbation of riboflavin metabolism pathways or exogenous depletion in physiological culture medium induce nucleotide imbalance and DNA damage responses, as well as impair the stability and activity of proteins which utilize [4Fe-4S] iron-sulfur clusters as cofactors. We identify a window of therapeutic opportunity upon riboflavin starvation or chemical riboflavin metabolism perturbation and demonstrate that this strongly synergizes with BCL-2 inhibition. Our work identifies riboflavin as a critical metabolic dependency in leukemia, with functions beyond energy production.
Authors: Stefan Bjelosevic, Rahel Fauth, Brian T. Do, Gabriela Alexe, Lucy A. Merickel, Thomas D. Jackson, Allen T. Basanthakumar, Audrey Taillon, Silvi Salhotra, Birgitta Ryback, Constanze Schneider, Giulia DiGiovanni, Ryan Elbashir, Nils Burger, Muhammad Bin Munim, Shan Lin, Pere Puigserver, David E. Root, Matthew G. Vander Heiden, Kimberly Stegmaier
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G4339824153, Characterizing the role of MARCH5 in apoptosis regulation in acute myeloid leukemia, Molecular determinants of fetal hemoglobin induction by hydroxyurea to treat sickle cell disease, G707340384, Cancer Center Support (Core) Grant, Targeting Pediatric Cancer Vulnerabilities, Understanding the role of metabolism in cancer
OpenAlex ID: W4411842528