{"doi":"10.1101/2020.06.30.177477","title":"KDM5 inhibition offers a novel therapeutic strategy for the treatment of <i>KMT2D</i> mutant lymphomas","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123848,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9697,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":568051,"name":"Lola Konali","orcid":null,"position":1,"is_corresponding":false},{"id":567373,"name":"Annalisa D’Avola","orcid":"0000-0003-4691-3131","position":2,"is_corresponding":false},{"id":567374,"name":"Karina Close","orcid":"0009-0003-4237-4617","position":3,"is_corresponding":false},{"id":567375,"name":"Alison Yeomans","orcid":"0000-0001-9125-0379","position":4,"is_corresponding":false},{"id":567376,"name":"Martin Philpott","orcid":"0000-0003-3632-0084","position":5,"is_corresponding":false},{"id":463986,"name":"James E. 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