Precision Targeting with EZH2 and HDAC Inhibitors in Epigenetically Dysregulated Lymphomas

摘要: Purpose: Both gain-of-function EZH2 mutations and inactivating histone acetyltransferases mutations, such as CREBBP EP300, have been implicated in the pathogenesis of germinal center (GC) derived lymphomas. We hypothesized that direct inhibition HDAC would be synergistic GC-derived Experimental Design: Lymphoma cell lines (n=21) were exposed to GSK126, an inhibitor, romidepsin, a pan-HDAC inhibitor. Synergy was assessed by Excess over Bliss. Western blot, mass spectrometry co-immunopreciptiation performed. A SU-DHL-10 xenograft model utilized validate vitro findings. Pre-treatment RNA-sequencing MetaVIPER analysis used infer protein activity. Results: Exposure GSK126 romidepsin demonstrated potent synergy lymphoma with dysregulation. Combination other inhibitors also suggesting class effect romidepsin. Dual led modulation acetylation methylation H3K27. The effects combination due disruption PRC2 complex secondary RbAP 46/48. common basal gene signature shared among characterized upregulation chromatin remodeling genes transcriptional regulators. This finding supported metaVIPER which revealed 1/2 DNMT associated activation. Conclusions: Inhibition is leads dissociation complex. Our findings support clinical translation dysregulated