Origin and migration of follicular lymphoma cells

Abstract

F ollicular lymphoma (FL) was described for the first time by Brill and Symmers in 1925. The primary cytogenetic lesion, the t(14;18) was identified in 1982, and the breakpoint at BCL2 in 1985. Based on observations that the t(14;18) originates from an erroneous recombination event in precursor B cells, 1 a model evolved in which the tumor develops linearly from such a precursor cell ( Figure 1A). Other cytogenetic events frequently accompany the t(14;18), and various authors have attempted to distinguish different subgroups of FL with differences in biological behavior, risk of transformation to an aggressive lymphoma, prognosis and overall survival on the basis of these additional events.2,3 Apart from these cytogenetic abnormalities not further discussed here, it is evident that FL represents a germinal center lymphoma with high expression of activation-induced deaminase (AID) and in consequence a pattern of ongoing somatic hypermutations of immunoglobulin (IG) loci. 4,5 This is not necessarily a continuous process since tumor cells may leave and (re)enter a germinal center and, in consequence, may periodically acquire novel somatic hypermutations of the IG genes. Indeed, by analysis of individual tumor cells or by molecular cloning of IGH rearrangements from a pool of tumor cells, it became evident that within each individual lymphoma not all tumor cells share the same somatic hypermutations. This implies subclonal evolution of the lymphoma, each clone being detectable by a unique fingerprint. Thus sampling of multiple (subsequent) lymph nodes of a FL patient might show different fingerprints of these mutations and this type of analysis may provide us with a "genealogical tree" of the individual lymphoma ( Figure 1B).The prototypic FL is a histologically low grade (grade 1 or 2) and clinically indolent lymphoma and affected patients have a median overall survival of approximately 7 years or longer. Of note the great majority of patients present with disseminated disease at the time of diagnosis implying an equally long or even longer period of subclinical disease. This is in line with the observations that approximately half of all healthy adult individuals harbor one or more B-cell clones with a t(14;18), only very few of these clones developing into clinically relevant disease. At present these cells are called "follicular lymphoma-like cells" or FLLC. [6][7][8] In fact occasional cells carrying these t(14;18) can already be identified in hyperplastic tonsils from children.9 Besides, so-called follicular lymphoma in situ (FLIS) lesions can be identified in less than 3% of all reactive lymph nodes. 10 In these lymph nodes, some germinal centers are focally involved by FL cells as detected by immunohistochemistry, polymerase chain reaction analysis and in situ hybridization for the t(14;18).Interestingly and in contrast to what was expected, these FLLC and likely also FLIS lesions represent expansions of lowaffinity IgM(D) expressing (post-germinal) memory B cells that have accumulated high loads of somatic ...

Early stages in the ontogeny of small B‐cell lymphomas: genetics and microenvironment

“…Altogether these findings indicate that the dissemination of t(14;18) clones and bone marrow homing occurs very early, before malignant transformation, suggesting early niches and clonal expansion. This is in line with clonal dynamic studies on malignant FL , which suggest that bone marrow could constitute a propitious niche for founder FL cells migrating from initial expansion in the primary site. Such common committed precursor cells would again invade the lymph node at relapse.…”

Minimal residual disease monitoring in early stage follicular lymphoma can predict prognosis and drive treatment with rituximab after radiotherapy

“…Thus, early stage FL can be considered the earliest phase of the multistep process of FL pathogenesis (Roulland et al , ; Klein & Dalla‐Favera, ; Kluin, ; Mamessier et al , ).…”

Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression

“…In this respect, our finding of highly mutated FLLCs in the BM is of particular significance. While not a homing niche for memory B cells, the BM is a frequent invasion site in FL, and it could represent an early niche for cancer stem cells (41), in line with reported cases of synchronous FL development in donor/recipient pairs after allogeneic BM transplantation (BMT) (19,20). Importantly, the detection of t (14;18) + precursor FL clones in prediagnostic blood samples several years before diagnosis (17,18,20) supports a scenario in which some FL precursors have already acquired the defining events necessary for clonal maintenance and ineluctable malignant progression, long before symptomatic FL manifestation.…”