Pathogenesis of Follicular Lymphoma (FL)

FL Arises from B-Lymphocytes

FL is an incurable, indolent (slow-growing) non-Hodgkin's lymphoma (iNHL) defined by the proliferation of malignant germinal center B lymphocytes.1,2

  • The germinal center is an area of lymph nodes and lymphatic tissues in which there is selection and proliferation of B cells that specifically recognize certain antigens2,3

Genetic Mutations in FL

  • Approximately 90% of cases of FL have a reciprocal chromosomal translocation that involves chromosomes 14 and 18, ie: t(14;18).4 A reciprocal chromosomal translocation is a genetic abnormality in which pieces from two different chromosomes trade places with each other
  • The t(14;18) translocation results in overexpression of the BCL2 gene5
    • BCL2 is an anti-apoptotic (cell death-inhibiting), proto-oncogene (a normal gene which, when mutated, becomes an oncogene that can contribute to cancer)5
    • BCL2 overexpression in germinal center B cells allows them to avoid apoptosis (programmed cell death), resulting in an accumulation of inappropriately conserved, long-lived B cells2,5

t(14;18) Translocation

  • The t(14;18) translocation alone is not sufficient for cancerous transformation of B cells, but rather is a “first hit” in a multistep, non-random series of genetic and epigenetic changes that lead to lymphoma5
  • FL lacking t(14;18) may contain genetic rearrangements of the BCL6 gene, trisomy 3, or BCL2 overexpression due to other molecular abnormalities4
  • Fluorescence in situ hybridization (FISH) and karyotyping are methods that can be used to detect chromosomal abnormalities like t(14;18) and BCL6 translocations in patients with FL6

Genetic Changes in Follicular Lymphoma

Immune Dysfunction in FL

FL is an incurable disease characterized by a defective immune microenvironment. Follicular lymphoma cells impair the function of numerous cells of the innate and adaptive immune response that normally would fight cancer.2

Tumor cells alter the antitumor immune response via several mechanisms described in the figure below.

Defective Immune Microenvironment in FL2,7-10

APC, antigen-presenting cell; NK, natural killer; Treg, regulatory T cell.

References: 1. Lymphoma Research Foundation. About Lymphoma: Follicular Lymphoma. https://www. lymphoma. org /aboutlymphoma/nhl/fl/. Accessed January 5, 2019.  2. Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of Follicular Lymphoma. J Clin Investig. 2012;122(10):3424-3431. 3. The Free Dictionary: Medical Dictionary. Germinal Center. Accessed November 19, 2018. 4. Leich E, et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood. 2009; 114:826-834. 5. Ott G, Rosenwald A. Molecular pathogenesis of follicular lymphoma. Haematologica. 2008;93(12):1773-1776. 6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V.4.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed July 10, 2019. To view the most recent and complete version of the guideline, go online to NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 7. Nicholas NS, et al. Tumor microenvironment (TME)-driven immune suppression in B cell malignancy. Biochimica et Biophysica Acta. 2016;1863(3):471-482. 8. Shafer D, Smith MR, Borghaei H, et al. Low NK cell counts in peripheral blood are associated with inferior overall survival in patients with follicular lymphoma. Leuk Res. 2013; 37(10): 1213-1215. 9. Ramsay AG, Clear AJ, Kelly G, et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood. 2009;114(21):4713-4720. 10. Yang ZZ, Grote DM, Ziesmer SC, et al. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J Clin Invest. 2012; 122(4):1271-1282.