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

Author

Listed:
  • Selina Troester

    (University of Veterinary Medicine Vienna)

  • Thomas Eder

    (University of Veterinary Medicine Vienna)

  • Nadja Wukowits

    (University of Veterinary Medicine Vienna)

  • Martin Piontek

    (University of Veterinary Medicine Vienna)

  • Pablo Fernández-Pernas

    (University of Veterinary Medicine Vienna)

  • Johannes Schmoellerl

    (University of Veterinary Medicine Vienna
    Research Institute of Molecular Pathology (IMP))

  • Ben Haladik

    (St. Anna Children’s Cancer Research Institute (CCRI)
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Gabriele Manhart

    (University of Veterinary Medicine Vienna)

  • Melanie Allram

    (University of Veterinary Medicine Vienna)

  • Margarita Maurer-Granofszky

    (St. Anna Children’s Cancer Research Institute (CCRI))

  • Nastassja Scheidegger

    (University Children’s Hospital Zurich, University of Zurich)

  • Karin Nebral

    (St. Anna Children’s Cancer Research Institute (CCRI)
    Labdia Labordiagnostik)

  • Giulio Superti-Furga

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Medical University of Vienna)

  • Roland Meisel

    (Heinrich-Heine-University)

  • Beat Bornhauser

    (University Children’s Hospital Zurich, University of Zurich)

  • Peter Valent

    (Medical University of Vienna
    Medical University of Vienna)

  • Michael N. Dworzak

    (St. Anna Children’s Cancer Research Institute (CCRI)
    St. Anna Children’s Hospital, Medical University of Vienna)

  • Johannes Zuber

    (Research Institute of Molecular Pathology (IMP)
    Vienna BioCenter (VBC))

  • Kaan Boztug

    (St. Anna Children’s Cancer Research Institute (CCRI)
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Florian Grebien

    (University of Veterinary Medicine Vienna
    St. Anna Children’s Cancer Research Institute (CCRI)
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

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.

Suggested Citation

  • Selina Troester & Thomas Eder & Nadja Wukowits & Martin Piontek & Pablo Fernández-Pernas & Johannes Schmoellerl & Ben Haladik & Gabriele Manhart & Melanie Allram & Margarita Maurer-Granofszky & Nastas, 2025. "Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59930-9
    DOI: 10.1038/s41467-025-59930-9
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