B cells transiently unlock their plasticity, risking lymphoma development

Immune cells called B cells make antibodies that fight off invading bacteria, viruses and other foreign substances. During their preparation for this battle, B cells transiently revert to a more flexible, or plastic, stem-cell-like state in the lymph nodes, according to a new preclinical study from Weill Cornell Medicine investigators. The results could help explain how many lymphomas develop from mature B cells rather than from stem cells, as many other cancers do, and guide researchers in developing better treatments.

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

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

Dr. Laurianne Scourzic, a former instructor of molecular biology in medicine, also co-led the work in collaboration with Dr. Ari Melnick, adjunct professor of medicine at Weill Cornell Medicine and director of the Josep Carreras Leukaemia 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, in which they cycle between two zones: In one zone, called the dark zone, B cells rapidly divide and mutate to make a random array of antibodies; then they move to the other zone, called the light zone, where they stop dividing and compete for selection from helper T cells in order to either form antibody-secreting cells or memory B cells, long-lived cells that help the body remember the antigen it encountered. If the B cells are not chosen for either of these options, they will undergo apoptosis (programmed death) or a minor fraction will recycle back for additional rounds of proliferation, mutation and selection.

These rapid and multidirectional changes are unusual in normal mature cells and prompted Dr. Apostolou’s team to hypothesize that the B cells might be reverting to a stem cell-like state during process. “We know these B cells are mature and terminally differentiated, but they have features reminiscent of stem cells,” Dr. Apostolou said. “This goes against the central dogma that cells lose their plasticity and stemness as they develop.”

The team employed stringent functional methods to test the plasticity of these cells and found that indeed, germinal center B cells have drastically higher capacity to reprogram to a stem cell-like state compared with other mature B cells. Further investigation revealed that only a small subset of the germinal center B cells, the ones that receive T cell help, acquire this plasticity, proving that this process is tightly regulated. Indeed, using various means to modulate the communication between B cells and T cells, the team could enhance or reduce B cell plasticity.

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

The team then examined associations with lymphoma patients. “All the signatures that we identified for this highly plastic state seem to be even further upregulated in many lymphoma patients, and they correlate with worse prognoses,” Dr. Apostolou said. “We believe that the normal, tightly regulated plasticity during immune reaction can be hijacked by specific mutations to promote lymphomagenesis or enhance fitness.” Mutations in histone H1 are one such example.

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

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Effie Apostolou.

This work was supported by the National Institutes of Health through grant numbers 1R01CA283327, GM107287, R35CA220499 and P01CA229086; the Starr Foundation through grant number 2021-033; the Mark Foundation for Cancer Research; the Leukemia & Lymphoma Society (now known as Blood Cancer United) through grant numbers LLS SCOR 7021-20, 7029-23 and 7027-23; the Institute for Follicular Lymphoma Innovation; the Lady Tata Memorial Fund through grant number LTMT 180526-01; and the Lymphoma Research Foundation through grant numbers LRF 200818-01 and LRF 220994-01.

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