|
| Status |
Public on Feb 17, 2025 |
| Title |
Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12 (Cut&Tag) |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
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.
|
| |
|
| Overall design |
Cut&Tag: H3K27ac and H3K4me3 CUT&Tag was perfromed in primary material from a NUP98::KDM5A patient-derived xenograft model and in a dTAG-NUP98::KDM5A AML cell line that was treated with dTAG13 for 8h to investigate changes in histone mark distribution upon fusion protein degradation.
|
| |
|
| Contributor(s) |
Troester S, Eder T, Wukowits N, Grebien F |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Feb 14, 2024 |
| Last update date |
Feb 18, 2025 |
| Contact name |
Thomas Eder |
| E-mail(s) |
Thomas.Eder@vetmeduni.ac.at
|
| Organization name |
University of Veterinary Medicine, Vienna
|
| Department |
Department for Biological Sciences and Pathobiology
|
| Lab |
Grebien Lab
|
| Street address |
Veterinaerplatz 1
|
| City |
Vienna |
| ZIP/Postal code |
A-1210 |
| Country |
Austria |
| |
|
| Platforms (2) |
|
