Epigenetic plasticity in germinal center B cells may help explain the development of lymphoma

Epigenetic plasticity in germinal center B cells may help explain the development of lymphoma

Immune cells, so-called B cells, produce antibodies that fight off invading bacteria, viruses and other foreign substances. B cells temporarily revert to a more flexible, or plastic, stem cell-like state in lymph nodes as they prepare for this battle, according to a new preclinical study from researchers at Weill Cornell Medicine. The findings could help explain how many lymphomas develop from mature B cells rather than stem cells, as is the case with many other cancers, and could help researchers develop better treatments.

The study, published Dec. 29 in Nature Cell Biology, reveals a paradox: When mature B cells are primed to produce antibodies, a highly specialized process, they temporarily gain plasticity, a property normally reserved for non-specialized stem cells. They do this by partially erasing their B cell characteristics and activating stem-like programs that are normally silenced in mature, differentiated cells. These are epigenetic changes, which means that the packaging of DNA is adjusted to regulate gene activity without changing the genetic information itself. Thus, the cells can turn these changes on or off as needed.

“Lymphomas are mostly caused by genetic mutations, but our study suggests that some of these mutations may exploit this epigenetic plasticity to drive tumor growth and fitness,” said Dr. Effie Apostolou, associate professor of molecular biology in medicine and member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Dr. Laurianne Scourzic, a former lecturer in molecular biology in medicine, also co-led the work with Dr. Ari Melnick, associate professor of medicine at Weill Cornell Medicine and director of the Josep Carreras Leukemia Research Institute in Barcelona.

B cell fountain of youth

After B cells encounter an antigen, a special environment called the germinal center forms around them in the lymph nodes, where they switch between two zones: In one zone, called the dark zone, B cells divide and mutate rapidly to form a random array of antibodies; Then they move to the other zone, called the light zone, where they stop dividing and compete to select helper T cells to form either antibody-secreting cells or memory B cells, long-lived cells that help the body remember the antigen it has encountered. If the B cells are not selected for either of these options, they will undergo apoptosis (programmed death) or a small proportion will be recycled for further rounds of proliferation, mutation and selection.

These rapid and multidirectional changes are unusual in normal mature cells and led Dr. Apostolou's team hypothesized that the B cells may revert to a stem cell-like state during the process.

We know that these B cells are mature and terminally differentiated, but they have features reminiscent of stem cells. This contradicts the central dogma that cells lose their plasticity and stem shape as they develop.”

Dr. Effie Apostolou, Weill Cornell Medicine

The team used rigorous functional methods to test the plasticity of these cells and found that germinal center B cells actually have a significantly higher ability to reprogram themselves into a stem cell-like state compared to other mature B cells. Further research revealed that only a small subset of B cells in the germinal center, those that receive T cell help, acquire this plasticity, proving that this process is tightly regulated. By using different means to modulate communication between B cells and T cells, the team could actually improve or reduce B cell plasticity.

Using single cell techniques, Dr. Scourzic found that the B cells that interacted with T helper cells showed reduced expression of B cell-specific genes, weakening their B cell identity, while reactivating stem and progenitor-like programs and regulatory elements that are normally repressed during development. In another experiment, researchers deleted a protein called histone H1, which is commonly mutated in lymphoma patients and normally keeps chromatin tightly packed in B cells. They observed an “opening” of chromatin and increased plasticity of all B cells in the germinal center, regardless of their interaction with T helper cells. “This result shows that there could be multiple pathways to this plasticity,” said Dr. Scourzic.

The team then examined connections with lymphoma patients. "All of the signatures we have identified for this highly plastic condition appear to be further upregulated in many lymphoma patients, and they correlate with worse prognoses," said Dr. Apostolou. “We believe that normal, tightly regulated plasticity during the immune response can be hijacked by specific mutations to promote lymphomagenesis or improve fitness.” An example of this are mutations in histone H1.

The current work highlights promising and targeted molecules and signaling pathways involved in B cell plasticity. Ultimately, identifying the mechanisms involved in B cell plasticity in the germinal center and their functional links to lymphoma mutations could help researchers find biomarkers that indicate which patients would respond better to therapies.

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