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Genetically driven immune microenvironment states associate with therapeutic responses in MYD88 mutant lymphomas [WES]

ABSTRACT: The interaction between lymphoma cells and immune microenvironment cells and the impact of this functional interplay on therapeutic responses remain unexplored. Here we utilized murine models with oncogenically active MYD88 and additional genetic lesions co-triggered at selected B-cell stages to generate human-like lymphomas harboring MYD88L265P mutation. Lymphomas exhibited behaviors ranging from clinically indolent small-cell tumors to aggressive diffuse large B-cell lymphoma (DLBCL). Thus, genetically diverse lymphoma cells employed distinct immune evasion mechanisms that shaped unique lymphoma microenvironment (LME) states, whereby clonally expanded T-cells functioned as a double-edged sword, either sustaining indolent lymphoma cell survival or promoting antitumor responses in DLBCL. Consequently, efficacy of standard-of-care and novel immunotherapies was determined by individual T-cell features. Furthermore, experimental targeting of newly identified immune mechanisms improved therapeutic responses in vivo. Our results elucidate genetically-driven LME landscapes that influence therapeutic outcomes across distinct lymphoma subtypes, providing a proof-of-concept for personalized treatment based on immune information.

ORGANISM(S): Mus musculus

PROVIDER: GSE288502 | GEO | 2026/09/03

REPOSITORIES: GEO

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Transcriptional profiling of Myd88 L252P germinal center B-cells

Project description: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.

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Pre-neoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma [scRNA-seq]

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