Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12
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View abstract on PubMed
Summary
This summary is machine-generated.Nucleoporin 98 (NUP98) fusion oncoproteins drive pediatric acute myeloid leukemia (AML). Targeting CDK12, a direct NUP98::KDM5A target, induces DNA damage and AML cell death, revealing a new therapeutic vulnerability.
Area Of Science
- Hematology
- Molecular Biology
- Epigenetics
Background
- Nucleoporin 98 (NUP98) fusion oncoproteins are key drivers of pediatric acute myeloid leukemia (AML), associated with poor prognosis.
- NUP98-fusion AML exhibits a distinct epigenetic signature, including enhanced accessibility of hematopoietic stem cell genes and activating histone marks.
Purpose Of The Study
- To identify epigenetic programs and transcriptional targets directly regulated by the NUP98::KDM5A fusion oncoprotein.
- To uncover direct NUP98::KDM5A target genes essential for AML cell proliferation.
- To identify actionable therapeutic vulnerabilities in NUP98::KDM5A-driven AML.
Main Methods
- Utilized a ligand-induced degradation model for NUP98::KDM5A in AML.
- Employed CUT&Tag and nascent RNA-seq to map epigenetic and transcriptional regulation.
- Performed genome-wide CRISPR/Cas9 screening to identify direct target genes.
Main Results
- Identified 12 direct NUP98::KDM5A target genes crucial for AML cell growth.
- Validated cyclin-dependent kinase 12 (CDK12) as a druggable target in NUP98::KDM5A-expressing AML.
- Demonstrated that CDK12 inactivation leads to increased DNA damage and AML cell death.
Conclusions
- NUP98::KDM5A directly regulates a core set of genes essential for AML pathogenesis.
- CDK12 represents a promising therapeutic vulnerability for AML patients with oncogenic NUP98 fusions.
- Targeting CDK12 offers a potential strategy to induce synthetic lethality in NUP98-fusion AML.
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