ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression

  • Nature. 2026 Apr;652(8111):1004-1015. doi: 10.1038/s41586-025-10005-1.
Siva Kumar Natarajan  1  2  3 ,  Joanna Lum  1  2  3 ,  James Haggerty Skeans  1  2  4 ,  Minal Nenwani  5  6  7 ,  Sanjana Eyunni  3  8 ,  Mateus Mota  1  2 ,  Jill M Bayliss  1  2 ,  Akash Deogharkar  1  2 ,  Erin Taya Hamanishi  1  9 ,  Matthew Pun  1  2  4 ,  Stefan R Sweha  1  2 ,  Simon Hoffman  1  2 ,  Eleanor Young  8 ,  Qiuyang Zhang  10  11 ,  Rijul Mehta  1  2 ,  Olamide Animasahun  5  6  12 ,  Pranav Narayanan  1  2 ,  Sushanth Sunil  1  2 ,  Abhijit Parolia  8  10  11 ,  Peter Sajjakulnukit  13 ,  Pooja Panwalkar  1  2 ,  Robert Doherty  9 ,  Madison Clausen  9 ,  Derek Dang  1  2  3 ,  Debra Hawes  14 ,  Fusheng Yang  14 ,  Mariarita Santi  15 ,  Alexander R Judkins  14 ,  Yelena Wilson  16 ,  Thomas Vigil  13 ,  Andrea Franson  9 ,  Richard M Mortensen  17 ,  Tatsuya Ozawa  18  19 ,  Andrea Griesinger  20  21 ,  Eric C Holland  18  19 ,  Nicholas K Foreman  20  21 ,  Kulandaimanuvel Antony Michealraj  22 ,  Sameer Agnihotri  23  24  25 ,  Michael Taylor  26 ,  Richard J Gilbertson  27  28 ,  Carl Koschmann  9  10 ,  Arul M Chinnaiyan  8  10  11  29 ,  Costas A Lyssiotis  10  13  30 ,  Deepak Nagrath  5  6  7  10  12 ,  Sriram Venneti  31  32  33  34
Affiliations
  • 1. Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 2. Chad Carr Pediatric Brain Tumor Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
  • 3. Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 4. Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 5. Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA.
  • 6. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 7. Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
  • 8. Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 9. Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
  • 10. Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 11. Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 12. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 13. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 14. Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine University of Southern California, Los Angeles, CA, USA.
  • 15. Anatomic Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 16. Department of Pathology, Akron Children's Hospital, Akron, OH, USA.
  • 17. Departments of Molecular and Integrative Physiology, Internal Medicine, and Pharmacology, University of Michigan, Ann Arbor, MI, USA.
  • 18. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 19. Seattle Tumor Translational Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 20. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 21. Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.
  • 22. Department of Neurosurgery, University of Pittsburgh School of Medicine and Cancer 97 Biology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
  • 23. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 24. John G. Rangos Sr Research Center, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 25. Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 26. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
  • 27. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • 28. Department of Oncology, University of Cambridge, Cambridge, UK.
  • 29. Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 30. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
  • 31. Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
  • 32. Chad Carr Pediatric Brain Tumor Center, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 33. Michigan Center for Translational Pathology, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
  • 34. Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA. [email protected].
PMID: 41639460 DOI: 10.1038/s41586-025-10005-1
Abstract

ZFTA-RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA-RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA+ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA+ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

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