Gobel, C.; Niccholai, R.; de Groot, M. H. P.; Jayachandran, J.; Traets, J. J. H.; Morris, B.; Song, J.-Y.; Azarang, L.; Kasa, E.; de Groot, D.; Kreft, M.; Kersten, M. J.; Aslam, M. A.; van Leeuwen, F.; Jacobs, H.

Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factor MYC and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GC B cells and closely resemble their cell of origin. Given the dependency of GC B cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCL cell lines and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the suppression of MYC target genes. The sum of all these alterations results in a cell-identity crisis, wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strictly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL.