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

Selina Troester, Thomas Eder, Nadja Wukowits, Martin Piontek, Pablo Fernández-Pernas, Johannes Schmoellerl, Ben Haladik, Gabriele Manhart, Melanie Allram, Margarita Maurer-Granofszky, Nastassja Scheidegger, Karin Nebral, Giulio Superti-Furga, Roland Meisel, Beat Bornhauser, Peter Valent, Michael N. Dworzak, Johannes Zuber, Kaan Boztug and Florian Grebien ()
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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
Ben Haladik: St. Anna Children’s Cancer Research Institute (CCRI)
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)
Giulio Superti-Furga: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Roland Meisel: Heinrich-Heine-University
Beat Bornhauser: University Children’s Hospital Zurich, University of Zurich
Peter Valent: Medical University of Vienna
Michael N. Dworzak: St. Anna Children’s Cancer Research Institute (CCRI)
Johannes Zuber: Research Institute of Molecular Pathology (IMP)
Kaan Boztug: St. Anna Children’s Cancer Research Institute (CCRI)
Florian Grebien: University of Veterinary Medicine Vienna

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59930-9

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