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.

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.

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases* / genetics
  • Cyclin-Dependent Kinases* / metabolism
  • DNA Damage
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Leukemic
  • Humans
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Mice
  • Nuclear Pore Complex Proteins* / genetics
  • Nuclear Pore Complex Proteins* / metabolism
  • Oncogene Proteins, Fusion* / genetics
  • Oncogene Proteins, Fusion* / metabolism
  • Retinoblastoma-Binding Protein 2
  • Transcription, Genetic

Substances

  • Nuclear Pore Complex Proteins
  • Oncogene Proteins, Fusion
  • Cyclin-Dependent Kinases
  • CDK12 protein, human
  • Nup98 protein, human
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2