IndraLab

"Analysis of target gene expression showed an overall attenuated transcriptional response in KMT2D mutant cell lines for important KMT2D targets such as the tumor suppressors genes TNFAIP3 and A20, NFKBIZ, FAS, and DUSP1 (XREF_FIG, XREF_SUPPLEMENTARY)."

"Inactivating KMT2D mutations,46,47 and gainof-function EZH2 mutations (a member of Polycomb-group proteins), mainly at tyrosine 641 (Y641) hotspot,23,28,48,49 promote GC proliferation and block differentiation by transcriptional suppression of tumor suppressor genes that regulate B cell development, including KMT2D targets TNFAIP3, SOCS3 and TNFRSF14 and EZH2 targets CDKN1A, CDKN2A, PRDM1, and IRF4.46,50-52 While it has long been assumed that mutations in epigenetic modifiers arise in GC, in vivo models have shown that the impact of KMT2D mutations is dependent on the stage of B cell development, whereby mutations in early precursor B cells are sufficient to initiate lymphoma while mutations arising at later stages of GC B cell development require additional genetic hits to support malignant transformation.46,47 Loss-of-function CREBBP mutations in FL have been shown to facilitate immune evasion by downregulating MHC class II expression, associated with reduced T cell infiltration.53 These inactivating mutations may also contribute to lymphomagenesis by impairing the acetylation of non histone proteins p53 and BCL6,26 with emerging data showing that the BCL6 / HDAC3 and SMRT complex maintain the suppression of CREBBP target genes, including MHC class II, in CREBBP-mutant cells, rendering HDAC3 inhibition as a potential therapeutic strategy by restoring histone H3 lysine 27 acetylation at target enhancers.54 More recently, global DNA methylation analysis of FL B cells has revealed hypermethylation of Polycomb suppressed genes and hypomethylation of heterochromatin regions compared with normal GC B cells."