2. Academic Validation
  3. Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12

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

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. florian.grebien@vetmeduni.ac.at.
  • 14 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria. florian.grebien@vetmeduni.ac.at.
  • 15 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. florian.grebien@vetmeduni.ac.at.
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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