Abstract The germinal center (GC) reaction is a tightly coordinated multicellular system in which B cells, T follicular helper (TFH) cells, follicular dendritic cells (FDCs), and macrophages orchestrate selection, affinity maturation, and clonal elimination. GC B cells give rise to the majority of non-Hodgkin lymphomas, yet how oncogenic epigenetic mutations subvert this system, not merely by conferring cell-intrinsic advantages, but by dismantling the GC architecture itself, remains poorly understood. Using intravital imaging in genetic mouse models, single-cell behavioral and transcriptional profiling, and spatial proteomics of human lymphoma biopsies, we show that oncogenic gain-of-function mutation in the histone methyltransferase EZH2 initiates a progressive, systems-level corruption of GC homeostasis that remodels every cellular compartment of the microenvironment. The epigenetic lesion first reprograms GC B cell behavior in vivo, increasing motility and morphological plasticity while redirecting migration toward FDC-rich light zone subregions. Mutant B cells maintain normal FDC engagement but shortened interactions and reduced surface engagement with TFH cells, requiring prior FDC contact before TFH interaction and impairing dark zone recycling. Transcriptionally, these cells upregulate metabolic and antigen-presentation programs while suppressing cell-death pathways, early signatures of survival fitness. This behavioral reprogramming cascades into broader niche corruption. Epigenetically altered B cells increase contacts with macrophages, converting them from active phagocytes into lymphoma-supporting cells with stellate morphology, loss of phagocytic identity, and an SPP1+MIF+BAFF+ program. Reprogrammed macrophages fail to perform trogocytosis of FDC membranes, driving FDC network expansion and increased immune complex deposition, while delivering pro-survival signals back to B cells via MIF, BAFF, and ICAM1-LFA1 engagement, completing a feedforward circuit reinforced at the lymphoma stage by BCL2. The result is a GC in which affinity selection thresholds are lowered, B cell survival is uncoupled from T cell help, and clonal elimination is suppressed. Macrophage depletion suppresses both pre-malignant expansion and established lymphoma, and spatial proteomics of human DLBCL and FL confirms enhanced macrophage–B cell proximity and dominant ICAM1-LFA1 signaling in epigenetically driven tumors. Therapeutically, macrophage reprogramming explains the failure of anti-CD47 monotherapy: the phagocytic machinery is silenced before the "don't eat me" signal becomes relevant. EZH2 inhibition restores phagocytic function, re-sensitizing tumors to anti-CD47 blockade in vivo. These findings reframe GC-derived lymphomagenesis as an emergent systems failure in which a single epigenetic lesion sequentially dismantles multicellular homeostasis, demonstrating that therapeutic design must target the ordered intercellular dependencies through which the aberrant niche is constructed. Citation Format: Wendy Béguelin. Epigenetic regulation of the lymphoma microenvironment: from single-cell behavioral reprogramming to systems-level niche corruption abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr IA008.
Wendy Béguelin (Wed,) studied this question.