Ruth Flümann

Gating strategies, validation of results using alternative models or definitions, QC controls, etc.

Supplementary Table S1 - Differentially expressed genes and PAGE analysis in Myd88 L252P GCB

A third of patients with diffuse large B-cell lymphoma (DLBCL) present with extranodal dissemination, which is associated with inferior clinical outcomes. 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 costimulation. Additionally, Myd88L252P skewed B cells toward 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.Significance:Extranodal lymphomas feature a very poor prognosis. The identification of phenotypically distinguishable prospective precursor cells represents a milestone in the pursuit of earlier diagnosis, patient stratification, 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.See related commentary by Leveille et al. (Blood Cancer Discov 2023;4:8–11).This article is highlighted in the In This Issue feature, p. 1

Table S4 contains the individual mutations of PPMBC and MBC lymphomas.

Table S6 contains clinical parameters and sequencing results of human DLBCL samples.

Table S3 contains B cell receptor repertoire sequencing data and lists the individual sublcones of the dominant clones of MBC, SMBC and PPMBC lymphomas.

Table S1 contains the p values of comparisons of the V gene usage in non-malignant GC B cells between the individual genotypes. These comparisons were done on the family, gene and allele level. V usage was compared for all BCR sequences as well as for isotype subsets.

This file contains the Supplementary Figures S1 to S12.