The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes (RNA-Seq)

ABSTRACT: Epigenetic regulators are frequently mutated in acute myeloid leukemia (AML). However, epigenetic dysregulation in AML extends beyond recurrently mutated factors and only little is known about the potential drivers in this context. Identification and characterization of novel epigenetic drivers impacting on AML biology will not only improve our basic understanding of AML but may also uncover novel options for therapeutic intervention. To uncover novel epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of CEBPA mutant AML. We identified the H3K4me2/3 demethylase KDM5C as a novel tumor suppressor in AML. We found that lower Kdm5c/KDM5C expression levels are associated with accelerated growth of human and murine AML cell lines. In a CEBPA mutant AML mouse model, Kdm5c knockdown resulted in a more aggressive, immature and short-latency phenotype. Mechanistically, we show that knockdown of Kdm5c increased H3K4me3-levels globally. This translated into the up-regulation of a group of bivalently marked immature genes resulting in a de-differentiation phenotype which could be reversed by modulating levels of pro-differentiating factors. Finally, we could demonstrate that low levels of KDM5C was associated with a decrease in long-term disease-free survival, specifically in female patients. This emphasizes the clinical relevance of our findings and identifies KDM5C as a novel sex-specific tumor suppressor in AML.

ORGANISM(S): Mus musculus

PROVIDER: GSE141476 | GEO | 2023/01/11

REPOSITORIES: GEO