GSE138032
EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [RNA-Seq]
The mechanism through which lymphoma-associated EZH2 gain-of-function mutations disrupt the immune system to initiate malignant transformation is poorly understood. Conditional expression of mutant Ezh2 in germinal center (GC) B-cells provides a competitive advantage to activated B-cells in expanding the GC light zone (LZ) that is not caused by failure to differentiate and exit the GC. Instead, the LZ enlargement is explained by reduced apoptosis of Ezh2 mutant centrocytes, aberrant LZ proliferation, and failure of these centrocytes to re-enter the dark zone (DZ). Ezh2 mutant GCs fail to engage T-cells and to undergo clonal diversification, exhibiting a reduced IgV mutation frequency. Hence the dominant competitive advantage effect of Ezh2 mutation during early stages of transformation is to uncouple GC B-cells from T-cell help checkpoint, which allows GC B-cells entering the LZ to persist and expand regardless of their immunoglobulin status, reflecting the biology of low-grade follicular lymphomas. Overall design: Twenty-four samples total: centroblast Ezh2(Y641F)fl/wt;C?1-cre (four biological replicates), centroblast C?1-cre (four biological replicates), centrocytes Ezh2(Y641F)fl/wt;C?1-cre (four biological replicates), centrocytes C?1-cre (four biological replicates), naïve B-cells Ezh2(Y641F)fl/wt;C?1-cre (four biological replicates), naïve B-cells C?1-cre (four biological replicates) of 3 months-old mice immunized with SRBC and euthanized 8 days post-immunization