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

• Published in: Nature communications Vol. 16; no. 1; pp. 4656 - 21
• Main Authors: Troester, Selina, Eder, Thomas, Wukowits, Nadja, Piontek, Martin, Fernández-Pernas, Pablo, Schmoellerl, Johannes, Haladik, Ben, Manhart, Gabriele, Allram, Melanie, Maurer-Granofszky, Margarita, Scheidegger, Nastassja, Nebral, Karin, Superti-Furga, Giulio, Meisel, Roland, Bornhauser, Beat, Valent, Peter, Dworzak, Michael N., Zuber, Johannes, Boztug, Kaan, Grebien, Florian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.05.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 38; 45; 49; 631/337/100/2285; 631/337/1427; 631/337/2019; 631/67/1990/283/1897; 64; Acute myeloid leukemia; Animals; Cell death; Cell Line, Tumor; CRISPR; CRISPR-Cas Systems; Cyclin-dependent kinase; Cyclin-dependent kinases; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Damage; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; Epigenesis, Genetic; Epigenetics; Gene Expression Regulation, Leukemic; Genes; Hematopoietic stem cells; Histones; Humanities and Social Sciences; Humans; Kinases; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; multidisciplinary; Nuclear Pore Complex Proteins - genetics; Nuclear Pore Complex Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncoproteins; Pediatrics; Retinoblastoma-Binding Protein 2; Science; Science (multidisciplinary); Stem cells; Transcription; Transcription, Genetic
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-59930-9

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. The epigenetic and transcriptional roles of Nucleoporin 98 (NUP98) fusion oncoproteins in driving pediatric acute myeloid leukemia (AML) remain to be explored. Here, the authors identify a core set of genes regulated by NUP98::KDM5A and suggest CDK12 as a potential therapeutic vulnerability.