EZH2 Y646

SC-2882 is a first-in-class specific QPCTL inhibitor that induces secondary proteolytic degradation of the monocyte chemoattractants CCL2 and CCL7 (da Silva, Nature Immunology 2022) and inactivation of the "do-not-eat-me" signal CD47 (Logtenberg, Nature Medicine 2019)...Additional analysis of LME cell subpopulations by SC-RNA-seq is ongoing. Overall, these data indicate that QPCTL is a potential target in DLBCL, and that QPCTL inhibition exhibits potent anti-lymphoma effects primarily by targeting the IN-LME.

In this study, we performed an in-depth spatio-temporal analysis of EZH2 mutations in FL using tissue- and liquid biopsy samples and identified gain-of-function mutations in a considerably higher proportion of patients than previously reported (42% vs 27%) owing to the ability of this approach to resolve spatial heterogeneity. This expands the subset of FL patients who most likely would benefit from EZH2 inhibitor therapy and highlights the need for parallel EZH2 testing in LB and TB samples when considering EZH2 inhibitor therapy. EZH2, ctDNA, Follicular lymphoma

While this aggressive subset is small, it is of particular therapeutic interest given the availability of EZH2 inhibitors and because overexpressed CTAs may also make it a candidate for immunotherapy. Legal entity responsible for the study The authors.

Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature.

For cell cycle analysis by flow cytometry, cells were treated, fixed then stained with 7-AAD. We designed and synthesized 2 dual EZH2/HDAC inhibitors, MC4343 and MC4355, starting from the structures of EZH2 inhibitor tazemetostat (taz) and HDACi vorinostat. We designed and synthesized 2 novel dual EZH2/HDAC inhibitors, MC4343 and MC4355, with robust anti-proliferative effects in DLBCL. Our data show the efficacy of this novel class of epigenetic agents in lymphomas.

The EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases). A high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.

Given the known early clonal nature of CREBBP mutations in FL and its role in regulating germinal center cycling, we speculate that CREBBP KAT mutations may limit the exposure of FL to the dark zone, reducing the opportunity for aSHM and creating an evolutionary constraint that may limit the opportunity for HT. This classification may serve as a useful biomarker to identify FLs at higher risk of HT.