2. Academic Validation
  3. OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis

OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis

  • Cell Metab. 2025 Oct 7;37(10):2014-2029.e9. doi: 10.1016/j.cmet.2025.08.008.
Christina Mayerhofer 1,  Dan Li 1,  Trine Kristiansen 1,  Ernst Mayerhofer 2,  Azeem Sharda 3,  Giulia Schiroli 1,  Karin Gustafsson 1,  Lingli He 1,  Michael Mazzola 3,  Sam Keyes 3,  Anna Kiem 3,  Eve Crompton 3,  Yanxin Xu 4,  Sovannarith Korm 4,  Zhixun Dou 5,  Charles Vidoudez 6,  Peter G Miller 7,  Nick van Gastel 8,  Timothy A Graubert 9,  David T Scadden 10
Affiliations

Affiliations

  • 1 Center for Regenerative Medicine and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
  • 2 Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 3 Center for Regenerative Medicine and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
  • 4 Center for Regenerative Medicine and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
  • 5 Center for Regenerative Medicine and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
  • 6 Harvard Center for Mass Spectrometry, Harvard University, Cambridge, MA, USA.
  • 7 Center for Regenerative Medicine and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
  • 8 de Duve Institute, UCLouvain, Brussels, Belgium; WELBIO Department, WEL Research Institute, Wavre, Belgium.
  • 9 Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA.
  • 10 Center for Regenerative Medicine and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: david_scadden@harvard.edu.
PMID: 40961937 DOI: 10.1016/j.cmet.2025.08.008
Abstract

Acute myeloid leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDXs) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting BCAAs further reduced chemoresistant AML cells, but relapse still occurred. Among the persisting cells, we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate- and iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA. We found that OGFOD1 upregulates protein synthesis in AML, driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML while sparing normal hematopoiesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation. Targeting OGFOD1 may offer a distinctive, translation-modifying means of reducing the chemopersisting cells that drive relapse.

Keywords

BCAA; OGFOD1; Ribo-seq; acute myeloid leukemia; chemoresistance; metabolism; protein biosynthesis; ribosome pausing; translation accuracy.

Figures
Products