KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]

Loss of function mutations within KMT2D are a striking feature of the germinal centre lymphomas, with lesions present in 80% of Follicular Lymphoma (FL) and 30% of Diffuse Large B-cell Lymphoma (DLBCL), resulting in decreased H3K4 methylation and altered gene expression. The KDM5 family normally maintains homeostasis through demethylating H3K4me3/2, thus negatively regulating gene expression. We hypothesised that inhibition of KDM5 may re-establish H3K4 methylation and restore the expression of genes repressed upon loss of KMT2D. Using a selective inhibitor of the KDM5 family we were able to increase H3K4me3 levels in DLBCL cell lines, predominantly at gene promoters, ultimately leading to decreased proliferation and cell death in KMT2D mutant cell lines. This appeared to be driven by an increase in the expression of negative regulators of B cell survival pathways, many of which have previously been described as targets of KMT2D and CREBBP, resulting in diminished BCR signalling. We also observed decreased BCL2 expression in all examined t(14;18) positive cell lines, alongside changes in other BCL2 family members in sensitive cell lines. KDM5 sensitivity was confirmed to be dependent on the presence of KMT2D mutations by generating de novo KMT2D mutant cell lines and correcting naturally mutant cell lines, which displayed greater and lesser sensitivity to KDM5 inhibition respectively. KDM5 inhibition may therefore be an effective therapeutic strategy for ameliorating KMT2D loss of function mutations in malignancies such as germinal centre lymphomas. The effect of KMD5i was examined on lymphoma cell lines using RNA-seq (n=3, 24 and 72 hours) and H3K4me3 ChIP-seq (n=2, 72 hours). KDM5 isoform expression was also quantified in FL patient samples