Pathogenesis of follicular lymphoma

Abstract

The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. Most tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. The sequence in which these events occur and how they contribute to progression and ultimately to transformation is unclear. Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.

Figures

Figure 1. A model of the microenvironment in FL.

Tumor cells are nurtured by a variety of cells (orange) such as FTH cells, FDCs, and follicular reticular cells (FRCs). Beneficial signals for growth and survival include cytokines such as IL-4 and IL-21, which bind to interleukin receptors on lymphoma cells (IL-4R/IL-21R) or CXCL12 and CXCL13 secreted by stromal cell subsets. BCR signaling occurs through stimulation of the BCR by the innate immune system through N-glycans or by specific antigen presentation through professional APCs such as FDCs. Tumor cells subvert the antitumor immune response from T helper cells, CTLs, and macrophages (purple). For example, FL cells prevent lysis through CTLs by inducing a T cell immunologic synapse dysfunction, or by secretion of IL-12 they induce T cell exhaustion. Immune cell subsets that suppress an efficient immunological response against the tumor include Tregs and M2 polarized macrophages (TAMs) (blue). The former are enriched in the FL microenvironment and dampen the T cell response. FL contributes to the preferential conversion of T helper cells into Tregs by proteins such as TGF-β or CCL22. Whereas classically activated TAMs (M1 polarized) control malignant growth through induction of a Th1 response, M2-polarized TAMs exert a tumor-promoting function through angiogenesis and induction of an immunosuppressive Th2 response.

Figure 2. A model of the complex pathways leading to progression and transformation in FL.

Evolution occurs through emergence of traits that provide a growth advantage under selective pressures such as therapy and tumor control by the microenvironment. The circles denote hits that drive somatic cells to malignancy. The progenitor cell may precede overt FL by many years and in roughly 85% of cases harbors a BCL2/IGH rearrangement in addition to putative secondary hits. The progenitor disseminates early during the course of the disease. Clinical FL develops with the acquisition of further genetic alterations and establishment of immune privilege. Relapse occurs either by direct clonal evolution from de novo FL or by indirect evolution from a common ancestral cell. Transformation is thought to develop along similar pathways, but may be dominated by one of a number of key genetic alterations.