Targeting DOT1L and EZH2 Synergizes in Breaking the Germinal Center identity of Diffuse Large B cell Lymphoma
Approximately 40% of Diffuse Large B cell Lymphoma (DLBCL) cases are refractory to or relapse by standard-of-care R-CHOP therapy, with limited therapeutic alternatives. Germinal Center (GC)B-DLBCL arises from GCB cells and closely resembles their cell of origin. Given the dependency of GC B cells on epigenetic writers DOT1L and EZH2 to establish and maintain their pro-proliferative cellular identity, we explored the role of these epigenetic writers as therapeutic targets for GCB-DLBCLs.
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Our data revealed a well-preserved cooperativity between DOT1L and EZH2 in establishing an epigenetic barrier important for GCB cell identity in MYC-rearranged DLBCL. Combined inhibition promotes the transition from a GCB cell phenotype into a so-called ‘plasma cell-like state’. This differentiation state is associated with the gain of BCL6 target genes, loss of MYC target genes, as well as compromised cell survival in 7 out of 9 tested GCB-DLBCLs in vitro. Importantly, the same synergistic effect was observed in vivo for GCB-DLBCL xenografts.
As corrupted cellular differentiation is a hallmark in the development of many types of malignant tumors, we propose a differentiation-based therapeutic strategy targeting DOT1L and EZH2 to epigenetically drive the differentiation of GCB-DLBCL into an anti-proliferative plasma cell-like state. Our findings not only highlight the role of DOT1L and EZH2 in maintaining the MYC-driven GCB cell identity in DLBCL through the cooperative repression of PRC2 target genes but also introduce a novel therapeutic approach for DLBCL treatment.