Pathway-Specific Dysregulation in Follicular Lymphoma Correlates to Histological Transformation

Follicular lymphoma (FL) is the most common low-grade non-Hodgkin lymphoma. Despite its indolent nature, FL carries an inherent risk of histological transformation (HT) to a more aggressive lymphoma. Existing clinicopathological features and biomarkers are insufficient to predict HT, indicating the need for more robust biological predictors. Previously, we used proteomics to identify differentially expressed proteins in FLs with and without subsequent HT. This study sought to further evaluate these by investigating identified proteins acting in important cellular pathways that could be divided into five major classes: (i) apoptotic regulation (BID), (ii) cell cycle progression (CDC26, CDK6, SRSF1, SRSF2), (iii) GTPase signaling (IQGAP2, MEK1), (iv) cytoskeletal rearrangement and cellular migration (ACTB, CD11a, MMP9, SEPT6), and (v) immune processes (CD81, IgG, MPO, PIK3AP1). We analyzed protein expression in pre-therapeutic lymphoma samples from 48 FL patients stratified as either non-transforming FL (nt-FL, n=30) or subsequently-transforming FL (st-FL, n=18) with histologically-confirmed transformation to diffuse large B-cell lymphoma. Paired transformed lymphomas (tFL, n=18) were also analyzed. We used immunohistochemistry and digital image analysis to quantify protein levels. In all five pathway classes, several proteins were differentially expressed between samples (p<0.05). Interestingly, we found correlation between expression levels of several proteins, indicating a complex interplay between the pathways. Differential expression of most proteins was also associated with shorter transformation-free survival (p<0.05). These findings emphasize underlying differences in FL biology, highlighting deregulation of interconnected cellular pathways, and suggest the potential mechanistic importance or predictive role of impaired cellular homeostasis, and altered microenvironment in FL transformation.

Honoré:Novo Nordisk A/S: Current equity holder in publicly-traded company; Genmab A/S: Current equity holder in publicly-traded company.