KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas
Heward JA., Konali L., D’Avola A., Close K., Yeomans A., Philpott M., Dunford J., Rahim T., Al Seraihi AF., Wang J., Korfi K., Araf S., Iqbal S., Bewicke-Copley F., Kumar E., Barisic D., Calaminici M., Clear A., Gribben J., Johnson P., Neve R., Okosun J., Oppermann U., Melnick A., Packham G., Fitzgibbon J.
<jats:title>Abstract</jats:title><jats:p>Loss-of-function mutations in <jats:italic>KMT2D</jats:italic> 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 <jats:italic>KMT2D</jats:italic>. KDM5-inhibition increased H3K4me3 levels and caused an anti-proliferative response <jats:italic>in vitro</jats:italic>, which was markedly greater in both endogenous and CRISPR-edited <jats:italic>KMT2D</jats:italic> mutant DLBCL cell lines, whilst tumour growth was inhibited in <jats:italic>KMT2D</jats:italic> mutant xenografts <jats:italic>in vivo</jats:italic>. KDM5-inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell receptor signalling and altered expression of BCL2 family members, including BCL2 itself, allowing it to synergise with agents targeting these pathways. KDM5-inhibition may offer an effective therapeutic strategy for ameliorating <jats:italic>KMT2D</jats:italic> loss-of-function mutations in GC-lymphomas.</jats:p><jats:sec><jats:title>Statement of significance</jats:title><jats:p>We detail a novel way of reverting the effects of loss-of-function mutations in the histone methyltransferase <jats:italic>KMT2D</jats:italic> by inhibiting the KDM5 demethylase family, increasing levels of H3K4me3 and restoring expression of KMT2D regulated genes.</jats:p></jats:sec>