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    Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas. © 2021 by The American Society of Hematology.


    James Heward, Lola Konali, Annalisa D'Avola, Karina Close, Alison Yeomans, Martin Philpott, James 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 Clear, John Gribben, Peter Johnson, Richard Neve, Pedro Cutillas, Jessica Okosun, Udo Oppermann, Ari Melnick, Graham Packham, Jude Fitzgibbon. KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas. Blood. 2021 Aug 05;138(5):370-381

    PMID: 33786580

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