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.
James Andrew Heward, Lola Koniali, Annalisa D'Avola, Karina Close, Alison Yeomans, Martin Philpott, James Edward Dunford, Tahrima Rahim, Ahad F Al Seraihi, Jun Wang, Koorosh Korfi, Shamzah Araf, Sameena Iqbal, Findlay Bewicke-Copley, Emil Kumar, Darko Barisic, Maria Calaminici, Andrew James Clear, John G Gribben, P W M Johnson, Richard Michael Neve, Pedro R Cutillas, Jessica Okosun, Udo Oppermann, Ari Melnick, Graham Packham, Jude Fitzgibbon