Submitted January 9, 2008
Accepted April 10, 2008
Reversible disruption of BCL6 repression complexes by CD40 signaling in normal and malignant B-cells
Jose M Polo, Weimin Ci, Jonathan D Licht, and Ari Melnick*
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States
Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, United States
Division of Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, IL, United States
* Corresponding author; email: amm2014{at}med.cornell.edu.
Germinal center (GC) B-cells undergo somatic hypermutation, class switch recombination and rapid clonal expansion in order to produce high affinity antibodies. The BCL6 transcriptional repressor facilitates this phenotype, since it can repress DNA damage checkpoint genes. GC B and T-cells can make transient direct physical contact and T-cells were observed to be associated with dead B-cell fragments. We wondered whether one function of CD40 signaling from T-cells within this timeframe could be to modulate BCL6 activity. We found that CD40 signaling rapidly disrupts the ability of BCL6 to recruit the SMRT corepressor complex by excluding it from the nucleus, leading to histone acetylation, RNA polymerase II processivity, and activation of BCL6 target genes such CD23b, ATR and p53. Washout of CD40 to emulate transient T-cell contact permitted BCL6 target gene mRNA levels to return to their repressed levels, demonstrating that this is a reversible process, which could allow centroblasts that pass quality control to either continue proliferation or undergo terminal differentiation. These data suggest that transient CD40 signaling in the GC might allow T-cells to weed out heavily damaged centroblasts while at the same time promoting survival of intact B-cells, which could undergo differentiation or additional rounds of proliferation.
