KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas.
Heward JA., Koniali L., D'Avola A., Close K., Yeomans A., Philpott M., Dunford JE., Rahim T., Al Seraihi AF., Wang J., Korfi K., Araf S., Iqbal S., Bewicke-Copley F., Kumar E., Barisic D., Calaminici M., Clear AJ., Gribben JG., Johnson PWM., Neve RM., Cutillas PR., Okosun J., Oppermann U., Melnick A., Packham G., Fitzgibbon J.
Loss-of-function mutations in KMT2D are a striking feature of the germinal centre (GC) lymphomas, resulting in decreased H3K4-methylation and altered gene expression. We hypothesised that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would re-establish H3K4-methylation and restore the expression of genes repressed upon loss of KMT2D. KDM5-inhibition increased H3K4me3 levels and caused an anti-proliferative response in vitro, which was markedly greater in both endogenous and CRISPR-edited KMT2D mutant DLBCL cell lines, while tumour growth was inhibited in KMT2D mutant xenografts in vivo. KDM5-inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signalling and altered expression of BCL2 family members, including BCL2 itself. KDM5-inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC-lymphomas.