Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12

  • Nat Commun. 2025 May 19;16(1):4656. doi: 10.1038/s41467-025-59930-9.
Selina Troester  1 ,  Thomas Eder  1 ,  Nadja Wukowits  1 ,  Martin Piontek  1 ,  Pablo Fernández-Pernas  1 ,  Johannes Schmoellerl  1  2 ,  Ben Haladik  3  4 ,  Gabriele Manhart  1 ,  Melanie Allram  1 ,  Margarita Maurer-Granofszky  3 ,  Nastassja Scheidegger  5 ,  Karin Nebral  3  6 ,  Giulio Superti-Furga  4  7 ,  Roland Meisel  8 ,  Beat Bornhauser  5 ,  Peter Valent  9  10 ,  Michael N Dworzak  3  11 ,  Johannes Zuber  2  12 ,  Kaan Boztug  3  4 ,  Florian Grebien  13  14  15
Affiliations
  • 1. Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
  • 2. Research Institute of Molecular Pathology (IMP), Vienna, Austria.
  • 3. St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
  • 4. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 5. Division of Oncology and Children's Research Centre, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • 6. Labdia Labordiagnostik, Vienna, Austria.
  • 7. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  • 8. Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
  • 9. Department of Internal Medicine I, Division of Hematology and Hemostaseologay, Medical University of Vienna, Vienna, Austria.
  • 10. Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
  • 11. Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria.
  • 12. Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.
  • 13. Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria. [email protected].
  • 14. St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria. [email protected].
  • 15. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [email protected].
PMID: 40389480 DOI: 10.1038/s41467-025-59930-9
Abstract

Nucleoporin 98 (NUP98) fusion oncoproteins are strong drivers of pediatric acute myeloid leukemia (AML) with poor prognosis. Here we show that NUP98 fusion-expressing AML harbors an epigenetic signature that is characterized by increased accessibility of hematopoietic stem cell genes and enrichment of activating histone marks. We employ an AML model for ligand-induced degradation of the NUP98::KDM5A fusion oncoprotein to identify epigenetic programs and transcriptional targets that are directly regulated by NUP98::KDM5A through CUT&Tag and nascent RNA-seq. Orthogonal genome-wide CRISPR/Cas9 screening identifies 12 direct NUP98::KDM5A target genes, which are essential for AML cell growth. Among these, we validate cyclin-dependent kinase 12 (CDK12) as a druggable vulnerability in NUP98::KDM5A-expressing AML. In line with its role in the transcription of DNA damage repair genes, small-molecule-mediated CDK12 inactivation causes increased DNA damage, leading to AML cell death. Altogether, we show that NUP98::KDM5A directly regulates a core set of essential target genes and reveal CDK12 as an actionable vulnerability in AML with oncogenic NUP98 fusions.

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