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Clonal evolution of follicular lymphomasFollicular lymphoma (FL) is an indolent subtype of non-Hodgkin's lymphoma (1) that clonally evolves over decades (2) before presenting as overt disease. In almost all cases of FL, the t(14;18)(q32;q21) translocation, which places the oncogene BCL2 under the control of the immunoglobulin heavy chain (IGH) enhancer, represents an initial genetic event (3-5). The juxtaposition of BCL2 to the J H cluster of the IGH locus confers a survival advantage on developmentally arrested germinal center (GC) B cells (6-8). Normal GC B cells do not express BCL2 and are characterized by a proapoptotic program of gene expression that includes cell surface death receptor FAS, tumor protein TP53, and BCL2-associated X (BAX) (9). Therefore, GC B cells are destined to die (9, 10) unless they are rescued by survival signals emanating from a B cell receptor (BCR) with high affinity to antigen. BCL2 expression is triggered in memory B cells that arise from a GC reaction and increases the half-life of these cells (11). As a consequence, transgenic mice that overexpress BCL2 in the hematopoietic compartment display a marked reduction of B cell apoptosis in GCs as compared with that seen in WT controls (12). Affinity maturation in these transgenic mice results in a memory B cell compartment with reduced stringency in the selection of high-affinity BCRs (12). These findings suggest that constitutive expression of BCL2 as the result of the t(14;18)(q32;q21) translocation fundamentally alters GC and memory B cell dynamics. Despite constitutive BCL2 expression, cooperating genetic lesions are required for malignant transformation of B cells into full-blown FL (7,8,13,14). The t(14;18) (q32;q21) translocation occurs at a low frequency in normal B cells in about 70% of healthy individuals and increases with age (15-18). Individuals in whom t(14;18) (q32;q21) translocation has occurred display developmentally arrested B cells (FL precursors) that have transitioned through the GC and have imprints of AID activity, namely somatic hypermutation (SHM) and class switch recombination (CSR) (16, 18). Full-blown FL arises from these atypical B cells decades later (2). The long latency period observed in FL development indicates a prolonged process of clonal evolution. Such a protracted clonal evolutionary process was previously demonstrated in a subset of pre-B cell acute lymphoblastic leukemia (ALL) patients who harbor the ets variant 6 runt-related transcription factor 1 (ETV6-RUNX1) translocation (19-21). Although the ETV6-RUNX1 rearrangement arises in utero (20), less than 1% of children who carry this rearrangement develop full-blown leukemia, which requires postnatal acquisition of secondary lesions in the preleukemic clone (21).Only recently have studies begun to elucidate the mechanisms responsible for the long latency period in FL evolution. Multiple studies have shown that IgM + memory B cells get reactivated and can reenter the GC upon antigenic recall (22-24). Importantly, GC ...
