PT  - JOURNAL ARTICLE
AU  - James A Heward
AU  - Lola Konali
AU  - Annalisa D’Avola
AU  - Karina Close
AU  - Alison Yeomans
AU  - Martin Philpott
AU  - James Dunford
AU  - Tahrima Rahim
AU  - Ahad F Al Seraihi
AU  - Jun Wang
AU  - Koorosh Korfi
AU  - Shamzah Araf
AU  - Sameena Iqbal
AU  - Findlay Bewicke-Copley
AU  - Emil Kumar
AU  - Darko Barisic
AU  - Maria Calaminici
AU  - Andrew Clear
AU  - John Gribben
AU  - Peter Johnson
AU  - Richard Neve
AU  - Jessica Okosun
AU  - Udo Oppermann
AU  - Ari Melnick
AU  - Graham Packham
AU  - Jude Fitzgibbon
TI  - KDM5 inhibition offers a novel therapeutic strategy for the treatment of <em>KMT2D</em> mutant lymphomas
AID  - 10.1101/2020.06.30.177477
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.30.177477
4099  - http://biorxiv.org/content/early/2020/07/02/2020.06.30.177477.short
4100  - http://biorxiv.org/content/early/2020/07/02/2020.06.30.177477.full
AB  - 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, whilst tumour growth was inhibited in KMT2D mutant xenografts in vivo. 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 KMT2D loss-of-function mutations in GC-lymphomas.Statement of significance We detail a novel way of reverting the effects of loss-of-function mutations in the histone methyltransferase KMT2D by inhibiting the KDM5 demethylase family, increasing levels of H3K4me3 and restoring expression of KMT2D regulated genes.Competing Interest StatementThe authors have declared no competing interest.