Mantle cell lymphoma (MCL) is a highly aggressive B cell lymphoma that accounts for 6% of all non-Hodgkin lymphomas and is characterized by abnormal proliferation of mature antigen- naive B lymphocytes. Despite recent advances in patient risk stratification, MCL remains incurable due to frequent relapses and resistance to therapy. SOX11 is a key transcription factor in the pathogenesis of MCL and is highly expressed in conventional MCL, but it is not expressed in the normal B cells or in the indolent leukemic nonnodal MCL subtype. Although SOX11 was identified as crucial oncogene that supports maintenance of MCL, its role in the initiation of MCL remains largely unknown. Here, we developed a novel mouse model for condition overexpression of SOX11 and a eGFP reporter and found that elevated levels of SOX11 in B-cells are sufficient to drive MCL-like lymphomas in mice. Moreover, SOX11 expression synergized with loss of p53 and overexpression of Ccnd2 to form aggressive MCL-like CD19+CD5+CD23IgM+IgD+ lymphomas, with a median survival of 314 (p53Mb1; n=11), 165 (SOX11/p53Mb1; n=19), and 134 (SOX11/Ccnd2/p53Mb1; n=15) days. These SOX11-driven lymphomas show transcriptional, immunophenotypic and functional similarities with both murine B1a cells and MCL patients. SOX11 overexpression skews B-cell development towards the B1a and marginal zone B-cell lineage and it block B2-cell development at the Pro-B and Pre-B cell stage, which coincides with onset eGFP that is a measure of expression of Cre and SOX11. In contrast to cyclin D2-driven MCL-like model, SOX11 is inducing a pre-lymphoma stage, in which there is a progressive accumulation of B1a cells in peripheral blood, peritoneal cavity, spleen and bone-marrow. The pre-lymphoma B1a cells have a BCR repertoire which was biased towards binding of self-antigens, such as phosphatidylcholine, and have increased BCR signaling activity. To prove that embryonic-derived B1a cells were the cell-of-origin of SOX11-driven MCL-like lymphoma, we transplanted CD19+ B-cells from SOX11/p53Mb1 fetal livers into secondary recipients and found that these embryonic cells could give rise to MCL-like lymphomas. Next, we wanted to determine how SOX11 is inducing the pre-lymphoma phase, either by expanding existing B1a cells, having a developmental bias towards B1a cells, or by the ability to reprogram B2-cells towards a B1a cell fate. Therefore, we crossed SOX11/p53 mice with a tamoxifen-inducible CreERT2 line and transplanted different sorted B1 and B2 subsets after a short tamoxifen induction ex vivo in immunocompromised mice. We found that SOX11 OE can redirect mature B2 cells to form B1a/MCL lymphomas. Overall, SOX11 is a key B1a lineage factor in mice and its aberrant expression is leading to the formation of MCL-like lymphomas in mice.

Citation Format: Tim Pieters, Steven Goossens, Pieter Van Vlierberghe. SOX11 drives B1a lineage commitment and B1a/MCL-like lymphoma formation in mice [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A26.