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

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Manhart, Gabriele; Tröster, Selina; Allram, Melanie; Fernandez Pernas, Pablo; Piontek, Martin; Grebien, Florian; Eder, Thomas

Abstrakt

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.

Dokumententyp

Originalarbeit

Open Access Type

Gold

WoS ID

WOS:001491378600032

Projekt

Common Oncogenic Mechanisms in Multi-Partner Translocation Families in Acute Myeloid Leukemia; Non-coding RNAs in oncogene-induced biomolecular condensates; Oncogenic biomolecular condensation in NUP98-fusion leukemia