How coupling data from mutation analyses and the complex clonal architecture yields insights in the clinical behavior of FL. (A) The complex clonal architecture of follicular lymphoma. (B) (a) The earliest step in the development of FL is acquisition of the IGH:BCL2 translocation. Cells carrying this lesion are frequently found in healthy individuals. Subsequent but still early steps in development of FL include mutations that disrupt regulation of chromatin structure, including mutations in EZH2 and MLL2. In this hypothetical patient, cells carrying just these mutations were not detected (red and blue cells with dashed borders) but their existence can be inferred from the detection of various cell populations carrying these same mutations as well as additional mutations (green, rose, and yellow cells with solid borders). Later events that are associated with HT include loss (or mutation) of TP53 and CDKN2A (yellow). It appears that in perhaps all cases that are studied with sufficiently sensitive techniques, the population that arises at HT (yellow) is not directly descended from the population detected at the time of diagnosis (green) or at relapse (rose). (b) The complex clonal architecture of FL raises 2 possible scenarios for the distribution of subclones at the time of diagnosis. Either the subclones are well mixed (a) or the subclones are relatively restricted to specific sites (b). For example, there is observational evidence that subclones in the marrow and the nodes are distinct and show only limited mixing in FL. At progression and transformation (c-d), the inhomogeneous distribution of subclones requires that selection of the biopsy site is based on clinical features or PET scan, so that the site of the aggressive subclone is sampled rather than a site composed of a low-grade subclone.