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

A third of patients with diffuse large B-cell lymphoma (DLBCL) present with extran-odal dissemination, which is associated with inferior clinical outcomes. MYD88L265P is a hallmark extranodal DLBCL mutation that supports lymphoma proliferation. Yet extranodal lym-phomagenesis and the role of MYD88L265P in transformation remain mostly unknown. Here, we show that B cells expressing Myd88L252P (MYD88L265P murine equivalent) activate, proliferate, and differen-tiate with minimal T-cell costimulation. Additionally, Myd88L252P skewed B cells toward memory fate. Unexpectedly, the transcriptional and phenotypic profi les of B cells expressing Myd88L252P, or other extranodal lymphoma founder mutations, resembled those of CD11c +T-BET+ aged/autoimmune mem-ory 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 defi ned prospective lymphoma precursor popula-tion and its dependencies, our findings pave the way for the early detection of premalignant states and targeted prophylactic interventions in high-risk patients.SIGNIFICANCE: Extranodal lymphomas feature a very poor prognosis. The identifi cation of phenotypi-cally distinguishable prospective precursor cells represents a milestone in the pursuit of earlier diag-nosis, patient stratifi cation, and prophylactic interventions. Conceptually, we found that extranodal lymphomas and autoimmune disorders harness overlapping pathogenic trajectories, suggesting these B-cell disorders develop and evolve within a spectrum.