Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12
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.
Authors
- Peter Valent (ORCID: https://orcid.org/0000-0003-0456-5095)
- Beat Bornhäuser (ORCID: https://orcid.org/0000-0003-2890-3191)
- Johannes Schmoellerl (ORCID: https://orcid.org/0000-0002-8461-8881)
- Martin Piontek
- Thomas Eder (ORCID: https://orcid.org/0000-0002-0932-2052)
- Pablo Fernández‐Pernas (ORCID: https://orcid.org/0000-0002-1305-1339)
- Kaan Boztuǧ (ORCID: https://orcid.org/0000-0001-8387-9185)
- Margarita Maurer‐Granofszky (ORCID: https://orcid.org/0000-0003-3519-9972)
- Roland Meisel (ORCID: https://orcid.org/0000-0001-5230-0628)
- Karin Nebral (ORCID: https://orcid.org/0000-0002-0548-541X)
- Ben Haladik (ORCID: https://orcid.org/0000-0001-6903-7379)
- Michael Dworzak (ORCID: https://orcid.org/0000-0002-8175-1097)
- Nastassja K. Scheidegger (ORCID: https://orcid.org/0000-0002-3091-2970)
- Giulio Superti‐Furga (ORCID: https://orcid.org/0000-0002-0570-1768)
- Gabriele Manhart (ORCID: https://orcid.org/0000-0001-8714-9550)
- Selina Troester (ORCID: https://orcid.org/0000-0001-6268-4442)
- Florian Grebien (ORCID: https://orcid.org/0000-0003-4289-2281)
- Johannes Zuber (ORCID: https://orcid.org/0000-0001-8810-6835)
- Melanie Allram (ORCID: https://orcid.org/0009-0009-9241-4107)
- Nadja Wukowits
Institutions
- Austrian Academy of Sciences (AT)
- University of Veterinary Medicine Vienna (AT)
- Research Institute of Molecular Pathology (AT)
- St Anna Children's Hospital (AT)
- CeMM Research Center for Molecular Medicine (AT)
- University Children's Hospital Zurich (CH)
- Vienna Biocenter (AT)
- St. Anna Children's Cancer Research Institute
- Heinrich Heine University Düsseldorf (DE)
- Community College of Rhode Island (US)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-19
- DOI
- https://doi.org/10.1038/s41467-025-59930-9
- Citations
- 4
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund
- Veterinärmedizinische Universität Wien