An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas.

A third of diffuse large B-cell lymphoma (DLBCL) patients present with extranodal dissemination, associated with inferior clinical outcome. MYD88L265P is a hallmark extranodal DLBCL mutation that supports lymphoma proliferation. Yet, extranodal lymphomagenesis and the role of MYD88L265P in transformation remain mostly unknown. Here, we show that B-cells expressing Myd88L252P (MYD88L265P murine equivalent) activate, proliferate, and differentiate, with minimal T-cell co-stimulation. Additionally, Myd88L252P skewed B-cells towards the memory fate. Unexpectedly, the transcriptional and phenotypic profiles of B-cells expressing Myd88L252P, or other extranodal lymphoma founder mutations, resembled those of CD11c+T-BET+ aged/autoimmune memory B-cells (AiBC). AiBC-like cells progressively accumulated in animals prone to develop lymphomas, and ablation of T-BET, the AiBC master regulator, stripped mouse and human mutant B-cells of their competitive fitness. By identifying a phenotypically-defined prospective lymphoma precursor population and its dependencies, our findings pave the way for the early detection of premalignant states and targeted prophylactic interventions in high-risk patients.