Intravital single-cell behavior profiling reveals disrupted germinal center B cell motility and interactions by EZH2 gain-of-function mutation

A study has revealed how a specific genetic mutation can significantly alter the behavior of germinal center B cells, potentially contributing to the development of non-Hodgkin lymphomas. Researchers examined the effects of a gain-of-function mutation in EZH2, a gene associated with lymphoma driver mutations, on the motility and interactions of these cells within the lymph node.

By employing a combination of intravital imaging, single-cell behavior analyses, and RNA sequencing, the team uncovered that EZH2 mutations in germinal center B cells led to increased speeds of cell movement and enhanced morphological plasticity. This altered behavior caused the cells to preferentially migrate towards the FDC-rich light zone of the lymph node, rather than the traditional dark zone.

Despite maintaining normal interaction quality with FDCs, these mutated cells exhibited shorter interaction periods and reduced surface engagement with T follicular helper (Tfh) cells.

The study also found that EZH2 mutant B cells required prior contact with FDCs before engaging with Tfh cells, a phenomenon that hindered the recycling of the diffuse zone (DZ). The frequency of this motility phenotype correlated with the local abundance of mutant clones, suggesting that this altered behavior provides a competitive advantage for mutant cells over wild-type counterparts.

Furthermore, the researchers developed a computational framework called scMOTIPh, which integrates single-cell behavioral features with transcriptomic profiles. Applying scMOTIPh to the mutant GC B cells within the FDC-rich zone revealed enhanced ATP production, metabolic and antigen-presentation programs, and suppression of cell-death pathways.

This pattern is consistent with a higher propensity for malignant transformation and increased survival fitness.

Overall, these findings provide a comprehensive in vivo, single-cell perspective on how an epigenetic mutation can rewire the local microenvironment by modulating single-cell behaviors within native germinal centers. This dynamic mechanism unveiled by the study offers valuable insights into the early stages of lymphomagenesis, shedding light on a novel strategy that may drive the progression of non-Hodgkin lymphomas.