IntroductionFollicular lymphoma (FL) is a slowly progressive and largely incurable human B-cell malignancy. Transformation to a more aggressive lymphoma, such as diffuse large B-cell lymphoma, is common and strongly associated with an increase in morbidity and mortality. A chromosomal translocation t(14:18) is the hallmark of this disease, and it is found in 85%-90% of cases. It results in the juxtaposition of the BCL2 proto-oncogene with the immunoglobulin (Ig) heavy chain gene, IGH, leading to deregulated overexpression of Bcl-2 protein, a major inhibitor of apoptosis. However, the t(14:18) translocation is insufficient to cause malignancy as it is detectable in rare B cells from healthy persons. 1-3 Thus, FL pathogenesis requires additional signals beyond that imparted by the deregulation of BCL2. The observation that FL cells isolated from patients fail to survive in vitro and undergo spontaneous apoptosis supports the hypothesis that extrinsic microenvironmental factors are required for maintenance and expansion of FL. 4 Phenotypically, FL tumor cells resemble antigen-experienced germinal center B cells. Their Ig genes, which are rearranged to produce a functional B-cell receptor (BCR), have numerous point mutations compared with their germline counterparts, and this process of somatic hypermutation (SHM) is ongoing as the malignant clone expands and diversifies. Thus, individual tumor cells can each have slightly different Ig variable region sequences. 5 Random mutations should eventually result in stop codons and loss of BCR protein expression. However, FL tumors maintain a surface BCR, indicating a selective force favoring retention of a functional BCR. Furthermore, therapy with anti-idiotype antibodies directed against the BCR did not select for the outgrowth of BCR-negative variants. Rather, this therapy selected for the outgrowth of cells that had amino acid substitutions in the targeted V region sequence, making them unrecognizable by the anti-idiotype antibody. 6 Other in vitro studies with malignant B-cell lines have shown that experimental knockdowns of the BCR and members of its signaling pathway result in growth arrest, implicating their importance in tumor cell survival. 7 The BCR can transmit a tonic survival signal, but this is greatly augmented on its binding to a cognate antigen. 8 There is indirect evidence to suggest that antigen recognition plays a role in the pathogenesis of FL. SHM can introduce silent or replacement mutations, the latter leading to an amino acid substitution. In a normal immune response, B cells with mutations resulting in higher binding affinity for the inciting antigen preferentially survive. This selective pressure leads to enrichment of replacement mutations in the complementarity determining regions (CDRs) of the BCR, and an under representation of replacement mutations in the framework regions (FWRs). 9 This same distribution of replacement and silent mutations has been reported for the BCRs of FL cells, 5 and the intraclonal diversity resulting from ongoing SHM...