Abstract
Greater than 75% of all hematologic malignancies derive from germinal center (GC) or post-GC B cells, suggesting that the GC reaction predisposes B cells to tumorigenesis. Because GC B cells acquire expression of the highly mutagenic enzyme activation-induced cytidine deaminase (AID), GC B cells may require additional DNA repair capacity. The goal of this study was to investigate whether normal human B cells acquire enhanced expression of DNA repair factors upon AID induction. We first demonstrated that several DNA mismatch repair, homologous recombination, base excision repair, and ATR signaling genes were overexpressed in GC B cells relative to naïve and memory B cells, reflecting activation of a process we have termed somatic hyperrepair (SHR). Using an in vitro system, we next characterized activation signals required to induce AID expression and SHR. Although AID expression was induced by a variety of polyclonal activators, SHR induction strictly required signals provided by contact with activated CD4+ T cells, and B cells activated in this manner displayed reduced levels of DNA damage-induced apoptosis. We further show the induction of SHR is independent of AID expression, as GC B cells from AID -/- mice retained heightened expression of SHR proteins. In consideration of the critical role that CD4+ T cells play in inducing the SHR process, our data suggest a novel role for CD4+ T cells in the tumor suppression of GC/post-GC B cells.
Highlights
Expression of select DNA repair pathway proteins is induced in germinal center (GC) B cells Gene targeting studies in mice have shown that DNA mismatch repair (MMR) genes are indispensable for somatic hypermutation (SHM), class switch recombination (CSR), and lymphoma suppression of B cells [9,22,23], and that even MMR haploinsufficient mice exhibit subtle phenotypes [9,23]
We hypothesized that the expression levels of MMR components and other DNA repair pathway proteins would increase in GC B cells and constitute the postulated somatic hyperrepair (SHR) apparatus
Mounting evidence has shown that expression of activation-induced cytidine deaminase (AID) in GC B cells poses a serious threat to genomic integrity and may induce oncogenesis unless there is additional DNA repair capacity
Summary
Among all types of hematologic malignancies, more than 75% of patients in the United States are classified as having nonHodgkin’s lymphomas, Hodgkin’s disease, chronic lymphocytic leukemia, or multiple myeloma [1,2]. The likely answer is that the GC reaction itself renders B cells highly susceptible to acquisition of non-immunoglobulin mutations and genomic instabilities [3,4,5,6,7], and functions as the ‘‘bottleneck’’ of the genetic wellness of B lineage cells Consistent with this notion, various cytogenetic abnormalities are notoriously associated with this group of malignancies. It remains unclear how the mutations and/or genomic instabilities that are the inevitable by-product of the genome-altering process of somatic hypermutation are suppressed during normal GC reactions, and how this tumor suppression mechanism fails in B lineage malignancies. To better understand these questions, it is essential to study in greater depth the mechanisms governing DNA repair in GC B cells
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