Aberrant MYC Levels Shape Germinal Centre Dynamics and Lymphoma Potential

Chromosomal translocations leading to MYC overexpression are frequently observed in germinal centre B (GCB) cell-derived lymphomas. Although concomitant stabilising mutations in MYC, such as T58A, are less common, they are found in aggressive lymphomas like Burkitt and double-hit lymphomas and are associated with poorer prognosis. Under physiological conditions, MYC is transiently induced in positively selected GCB cells within the light zone (LZ), following B cell receptor (BCR) stimulation and T cell help (TCH). How pathological MYC levels reshape GCB cell dynamics and promote lymphomagenesis remains unclear. To mimic chromosomal translocation-driven MYC overexpression, we adopted novel mouse models enforcing either wild-type MYC (MYCWT) or the stabilising T58A mutant MYC (MYCT58A) in GCB cells. Surprisingly, while MYCWT triggered transient GC hyperplasia, MYCT58A did not. Instead, MYCT58A drove long-term accumulation of GCB cells and accelerated GCB cell lymphomagenesis. Although MYCT58A cells proliferated more than MYCWT, their higher apoptosis and altered FOXO1 regulation likely underpinned the loss of transient hyperplasia. Functionally, CITE-seq revealed enhanced proliferation and metabolism in MYCWT and MYCT58A GCB cells, accompanied by reduced activity in signalling pathways associated with positive selection. However, MYCWT and MYCT58A only protected GCB cells from transient but not sustained TCH deprivation, suggesting continued reliance on survival signals like mTOR. Notably, flow cytometry and CITE-seq demonstrated enrichment of an intermediate LZ-dark zone (DZ) phenotype in MYCT58A GCB cells. These intermediate LZ-DZ cells were metabolically active, whose transcriptional signatures were enriched in human B cell lymphomas, correlating with malignant subtypes Burkitt and double-hit lymphomas. This phenotype also corroborated the enrichment of CCND3 mutations in human Burkitt Lymphomas, particularly when concurrent with MYC stabilising mutations, suggesting selection for mutations that promote DZ programme during MYCT58A-driven lymphomagenesis. Together, these findings revealed how MYCWT and MYCT58A differentially remodel GC dynamics, transcriptional programmes, and metabolic dependencies, thereby promoting GCB cell lymphomagenesis.