Early Steps of Follicular Lymphoma Pathogenesis

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western world, generally characterized by a disseminated disease at diagnosis, an indolent clinical course and recurrent, increasingly chemo-resistant relapses. Overt FL is preceded by an insidious phase of asymptomatic growth and might emerge from common precursor clones (CPCs), evolving over decades, and which might participate to subsequent relapses. Consequently, the cell of origin remains ambiguous. From the clinical standpoint, morphological, histological and molecular evidences all indicate that FL results from the malignant transformation of germinal center (GC) B-cells. Nevertheless, it is now clear that the natural history of FL does not initiate in the GC, and that FL precursors emerge much earlier in B-cell ontogeny. The hallmark t(14;18)(q32;q21) translocation, present in 85-90% of FL patients, results from repair failures during V(D)J recombination in bone marrow pre-B cells, and the ensuing constitutive expression of the BCL2 oncogene is thus considered the necessary early first hit to transformation. However, BCL2 as such is a very weak driver, as evidenced by the detection of t(14;18)in peripheral blood from a large fraction of the adult healthy population, and the long latency and low penetrance observed in various BCL2 mouse models. Intriguingly, circulating t(14;18)⁺-carrying cells in healthy individuals are mostly clonally expanded GC-experienced B cells, and show imprints of early illegitimate genomic events. Recent data of clonal dynamics in human and mouse models strongly suggest that such illegitimate events likely accumulated over iterative passages through successive GC reactions. Because GCs constitute a very particular environment, highly and purposely prone to genomic reshuffling and somatic mutations, such chronic "GC addiction" combined with BCL2-mediated decoupling from the GC selection checkpoint would create a highly mutagenic dynamics linked with slow oncogenic progression. Thus, the path to transformation appears as a complex multi-hit process occurring along B cell ontogeny, escalating along successive derailments of B cell receptor diversification mechanisms, and subversion of specific immunological properties of B cells. Combined with the power of next generation sequencing, molecular interrogations of t(14;18)⁺ clones in healthy individuals and FL patients recently provided new insights into CPCs, their commitment to malignant development years ahead disease manifestation, and into candidate genes paving the transformation process. Intriguingly, it is now envisioned that some of the recurrent alterations found in FL patients (such as KMT2D loss of-function) might occur in CPCs or earlier in B cell ontogeny and might even precede and/or condition t(14;18) occurrence or BCL2-mediated transformation. An exciting era is now opening in deciphering the kinetics of transformation and in decrypting the genomic status of FL CPC. With the prospective arrival of the chemo-free era in hematology and a flourishing landscape of novel therapeutic agents, it is today more important than ever to correctly understand the underlying FL biology in order to deliver efficient tailored therapies at the right time and in the right patients.