Ezh2-Y641F mutations are distinct from EZH2 overexpression and impact germinal center B cells in a timing-dependent manner

To determine whether Ezh2Y646 mutations and EZH2OE are functionally equivalent or distinct gain-of-function events in GC B cells, we directly compared EZH2Y641F/+ and EZH2OE using conditional mouse models that activate these events either throughout the B lineage or specifically within GC B cells.

Across transplant and non-transplant settings, we found that EZH2OE yields surprisingly weak phenotypes, while EZH2Y641F/+ causes strong but timing-dependent effects in GC cells. We observed that GC-specific EZH2Y641F/+ causes GC expansion and promotes lymphoma phenotypes, whereas early B lineage activation reduced GC fitness. Furthermore, transcriptional analysis and H3K27me3 profiling revealed that EZH2OE and EZH2Y641F/+ are non-equivalent molecular events.