TBL1XR1 mutations bias germinal center B-cells towards a pro-tumorigenic memory fate

Diffuse large B-cell lymphomas (DLBCL) encompass a heterogeneous group of diseases derived from different stages of B-cell differentiation. The most clinically aggressive forms of DLBCL, C5/MCD, carry activating mutations in canonical B-cell signaling pathways, as well as early-occurring hits in the poorly-characterized gene TBL1XR1. Here, we investigated the role of TBL1XR1 mutations in the early steps of malignant transformation. We found that TBL1XR1 mutations disrupt germinal center development, and introduce a cell fate bias towards memory B (MB) cells. At the molecular level, TBL1XR1 mutations trigger a switch, by which the SMRT/HDAC3 co-repressor complex shuttles between the lineage-defining transcription factors BCL6 and BACH2. We further demonstrate that terminal differentiation of TBL1XR1 mutant MB is limited upon recall, and that these MB re-enter the germinal center reaction instead, suggesting a role for these cells as the cell-of-origin of C5/MCD DLBCL. Overall design: RNAseq results of Tbl1xr1 murine model systems