The most aggressive B-cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response towards generating abnormal immature memory B-cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes towards binding the MB cell transcription factor (TF) BACH2, at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic re-entry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.

Citation Format: Leandro Venturutti, Matt Teater, Andrew Zhai, Amy Chadburn, Leena Babiker, Daleum Kim, Louis Staudt, Michael Green, Pedro Farinha, Andrew Weng, Christian Steidl, Ryan Morin, David Scott, Gil Privé, Ari Melnick. TBL1XR1 mutations drive extranodal lymphomagenesis by inducing a protumorigenic memory B-cell fate [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-42.