Abstract:
Follicular Lymphoma (FL) is a genetically and transcriptionally heterogeneous disease. Classic FL is characterized by t(14;18) (FLpos), while the pathogenesis of t(14;18)-negative FL (FLneg) remains less defined. Recent studies have shown that FLneg could be divided in those with STAT6/SOCS1 mutations and a group of FLneg without recurrent mutations. While these genetic differences are well described, their functional and transcriptional consequences in FLneg remain poorly understood. Therefore, we performed comprehensive gene expression profiling (GEP) using HTG and NanoString platforms to investigate the impact of STAT6/SOCS1 mutations on the transcriptional profile of FLneg. Our cohort represents the largest to date for FLneg GEP and was divided into 37 FLnegm (STAT6/SOCS1 mutated), 14 FLnegwt (wild-type) and 8 FLposm (BCL2 rearranged and STAT6/SOCS1 mutated). We confirmed the strong association between STAT6/SOCS1 mutations and CD23 expression in FLneg, underlining IL4/JAK/STAT6 pathway activation as key driver of CD23 upregulation. Here, FLpos showed a difference and appeared to be driven primarily by paracrine IL4 signaling from the tumor microenvironment. Using differential gene expression analyses, we found a distinct transcriptional program in FLnegm, characterized by persistent germinal center markers, STAT6 target genes, and immune modulation signatures, which suggest a post-activated germinal center phenotype. On the other hand, signatures of terminal B-cell differentiation and an immunologically active microenvironment in FLnegwt were identified, which included upregulation of IRF4 and SLAMF7. Unsupervised clustering revealed transcriptional subgroups within FLnegm, suggesting heterogeneity in STAT6 pathway activation. Different pathway activation is likely caused by mutational burden and co-mutations. Also, FLnegwt showed heterogeneous expression profiles, including cases with high SLAMF7 and FCRLA expression. These cases are probably linked to a more differentiated B-cell state. Finally, our findings support a model in which constitutive STAT6 pathway activation in FLnegm impairs terminal differentiation and sustains a GC-like phenotype, whereas FLnegwt retains the ability to differentiate. Our findings refine the current understanding of FLneg molecular stratification and propose a differentiation-based model of pathogenesis driven by IL4/JAK/STAT6 signaling. Extended subtype groups and functional validation are needed for further investigation.
