Follicular lymphoma: too many reminders for a memory B cell

Abstract

Memory B cells are a dynamic subset of the mature B cell population that in some cases can reenter germinal centers (GCs) in response to iterative infections. Such a reactivation can lead to accumulation of genetic lesions in these cells, potentially from repetitive activation of the B cell mutator enzyme AID. Normal memory B cells do not survive repeated reentries into GCs. In this issue, Sungalee et al. demonstrate that memory B cells harboring the oncogenic BCL2:IGH translocation, which results in constitutive BCL2 expression, survive multiple GC entries upon repetitive immunization. Through these multiple GC reentries, the hallmark BCL2:IGH translocation enables AID-induced hypermutation and propagates clonal evolution toward malignant follicular lymphoma.

Figure 1. Memory B cell dynamics in the multistep development of follicular lymphoma.

(A) Normal and t(14;18)⁺ naive B cells both enter into GC reactions upon immunization. GC B cells undergo SHM and CSR. Owing to constitutive BCL2 expression, t(14;18)⁺ cells have a survival advantage over normal GC B cells; therefore, BCL2-overexpressing t(14;18)⁺ cells are positively selected into the IgM⁺ memory B cell pool and are capable of GC reentry upon reexposure to antigen. With every successive cycle of GC reentry, t(14;18)⁺ cells outgrow their healthy counterparts. (B) Decades of iterative GC reentries cause an accumulation of abnormal t(14;18)⁺ cells in the GC (termed FLIS). This process produces a continuous output of t(14;18)⁺ IgM⁺ memory B cells, ultimately leading to overt FL.