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<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>

Original publication

DOI

10.1101/2020.06.30.177477

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

02/07/2020