N-glycosylation motifs. These motifs can interact with stromal elements in the microenvironment, thereby promoting survival and/or proliferation of tumor cells as well. 14-16 Most essentially, since FLLC and FLIS cells, like fully neoplastic FL cells, may also undergo multiple rounds of somatic hypermutation upon re-entry into germinal centers, this implies that somatic hypermutations as observed in FL are not necessarily produced in the malignant FL cells themselves but can also be generated earlier. This model with FLLC and/or FLIS as an intermediate step in lymphomagenesis (Figure 1C) is very difficult to prove in vivo, with only extremely rare observations supporting it (see below). The publication by Wartenberg et al. in this issue of the journal17 complements these observations. These authors studied the somatic hypermutation pattern of tumor cells in lymph nodes and bone marrow from three FL patients. In one patient a synchronous biopsy of the lymph node and bone marrow was investigated, in the two other patients two and five metachronous biopsies with a maximal interval of 3 years were taken. Using a novel mathematical approach the authors designed both compartment (lymph node/bone marrow) specific pedigrees, as well as a more global pedigree for the entire patient. Based on these calculations, they propose that FL cells start expanding within lymph nodes but may migrate early to the bone marrow and may stay there for long periods, likely years, in a relatively quiescent or dormant state. From the bone marrow these relatively less mutated “founder” FL cells may again invade the lymph nodes at relapse, giving support for bidirectional instead of unidirectional migration (Figure 1D). These data are in line with a previous publication18 also showing that bone marrow lymphoma cells may represent relatively early subclones. However, using a more conventional algorithm, those authors were not able to determine the exact direction of the migration of cells (migration from or to the bone marrow or vice versa).

In fact these novel observations fit well in a model in which the bone marrow provides a niche for the neoplastic cells, allowing them to survive and repopulate the body again, even after chemotherapy. Indeed a bone marrow-specific niche has already been proposed by several groups. 18-20 In consequence it could even be that clonally related and bone marrow-resident FLLC, instead of fully malignant FL cells, cause a relapse of lymphoma (Figure 1E).