Simplified model of FL evolution and progression based on the high-throughput sequencing of the immunoglobulin heavy chain variable gene and N-gly analysis. After the t14;18 translocation during a likely error in VDJ recombination in the bone marrow, the B cell migrates to the germinal center, where it undergoes SHM. N-gly sites are acquired early on in the process (purple figure) in the presumed precursor lesion, ISFN. As FL-like B cells are believed to represent the circulating counterparts of ISFN, N-gly sites also may be retained in these cells. Precursor cells that do not acquire sites through SHM undergo clonal deletion, assumed by the low frequency of site-negative subclones in the clonal repertoire. Clones maintain conservation of N-gly sites during tumor evolution through ongoing SHM and gain of additional mutations, leading to an ancestral cell pool population, the CPC. With the exception of patient 5, the CPC provides a reservoir from which distinct disease events arise, which retain the N-gly site. At each stage of evolution, SHM results in the emergence of clones that lose N-gly sites because of the largely random nature of the process that does not distinguish between favorable and nonfavorable mutations. However, these represent only a minor mass of the heterogeneous tumor population, and with the exception of patient 3, cannot traffic between events, indicating their insignificance in propagating progression and their likely loss from the clonal repertoire through cell death pathways. PFL, partial involvement by FL.