TBL1XR1 Mutations Bias toward Memory B-cell Fate to Promote Lymphoma

An aggressive subtype of activated B-cell diffuse large B-cell lymphomas (ABC-DLBCL) with an unusual extranodal distribution is characterized by mutations in the poorly understood gene TBL1XR1. Venturutti and colleagues discovered that a missense mutation in Tbl1xr1 found in these lymphomas and some developmental disorders diminished the germinal center reaction in mice. Further investigation revealed that this missense mutation mimicked complete Tbl1xr1 loss of function. Proliferation in germinal centers was impaired by Tbl1xr1 mutation, explaining the lower levels of germinal center B cells in Tbl1xr1-mutant and Tbl1xr1-knockout mice. Tbl1xr1-mutant mice exhibited elevated levels of precursor memory B cells, leading to bias toward the generation of memory B cells and away from the generation of plasma cells. Mechanistically, TBL1XR1 is a key part of the SMRT–NCOR1 transcriptional corepressor complex, and TBL1XR1-mutant human cells exhibited increased association of this complex with the memory B cell–associated transcription factor BACH2 over the germinal center–associated transcription factor BCL6, explaining why loss of TBL1XR1 function shifts the balance between memory B cells and plasma cells toward the former cell type. Upon antigen recall, Tbl1xr1-mutant memory B cells, rather than differentiating into plasma cells, exhibited a bias toward reentering the germinal center reaction, becoming germinal center B cells. Importantly, this demonstrates that lymphoma-associated mutations can direct B cells toward undergoing repeated cycles of mutagenesis, supporting the idea of cyclic immune stimulation as a driver of lymphomagenesis. Notably, Tbl1xr1-knockout mice developed lymphomas with marked similarities to human TBL1XR1-mutant ABC-DLBCLs. Consistent with the cyclic reentry notion, these lymphomas harbored abundant AID-associated somatic mutation, a genetic hallmark of extranodal ABC-DLBCLs. Finally, immunohistochemical analysis and mass cytometry supported the notion that human TBL1XR1-mutant ABC-DLBCLs also arise from memory B cells. In summary, this work uncovers a mechanism by which disease-associated mutations in the little-understood gene TBL1XR1 promote the development of aggressive lymphomas with extranodal distribution and points to memory B cells as the cell type of origin for this disease subtype.

Venturutti L, Teater M, Zhai A, Chadburn A, Babiker L, Kim D, et al. TBL1XR1 mutations drive extranodal lymphoma by inducing a pro-tumorigenic memory fate. Cell 2020;182:297–316.e27.

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