Characterizing and Targeting Follicular Lymphoma's Common Progenitor Cells

Follicular lymphoma (FL) is the most prevalent low-grade germinal centre (GC) derived non-Hodgkin lymphoma. Despite being considered an indolent lymphoma its clinical course is heterogenous with some patients experiencing frequent relapses and eventual transformation to a high-grade disease associated with an especially poor prognosis.

Through phylogenetic analysis of successive human FL tumors, evidence has emerged regarding the existence of common progenitor cells (CPCs). These precursor cells serve as a reservoir of cells that are able to evade killing with standard treatments for FL and give rise to relapse and transformed FL. They carry the t(14:18) translocation and are enriched for somatic mutations in chromatin-modifying genes including CREBBP and KMT2D. Developing therapies to specifically target and eliminate these common progenitor cells will be crucial in finding a cure for FL.

To understand this population of therapy-resistant precursor cells, we engineered mouse models that faithfully replicate the early and recurrent gene mutations observed in FL, including BCL2 translocation, CREBBP and KMT2D loss-of-function (LoF) mutations (BCK mice). We then subjected mice to a standard human-like treatment regimen of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone). Administration of the mouse-adapted R-CHOP resulted in the complete depletion of B cells from control mice. However, treatment of BCK mice revealed a resistant B-cell population. Notably, these resistant cells predominantly displayed a memory B-cell phenotype.

Single cell RNA-seq analysis of these therapy-resistant cells identifies unique transcriptional signatures and enrichment of pathways that can be targeted therapeutically. Comparison with human FL scRNAseq datasets shows that these therapy-resistant precursor cells are enriched in FL tumors of patients with early relapse.

Finally, we have used an innovative in vitro platform that harnesses a GC B-cell culture system to amplify CPCs, facilitating subsequent high-throughput drug screening. This approach has allowed us to identify specific vulnerabilities within the CPC population, paving the way for the development of therapies tailored to overcome FL resistance mechanisms.

Through these concerted efforts, we edge closer to the long-awaited goal of discovering a definitive cure for Follicular Lymphoma.