Follicular lymphoma B cells exhibit heterogeneous transcriptional states with associated somatic alterations and tumor microenvironments

Abstract

Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma of germinal center origin, which presents with significant biologic and clinical heterogeneity. Using RNA-seq on B cells sorted from 87 FL biopsies, combined with machine-learning approaches, we identify 3 transcriptional states that divide the biological ontology of FL B cells into inflamed, proliferative, and chromatin-modifying states, with relationship to prior GC B cell phenotypes. When integrated with whole-exome sequencing and immune profiling, we find that each state was associated with a combination of mutations in chromatin modifiers, copy-number alterations to TNFAIP3 , and T follicular helper cells (Tfh) cell interactions, or primarily by a microenvironment rich in activated T cells. Altogether, these data define FL B cell transcriptional states across a large cohort of patients, contribute to our understanding of FL heterogeneity at the tumor cell level, and provide a foundation for guiding therapeutic intervention. • B cells from follicular lymphoma exhibit 3 distinct transcriptional states • FL B cells differ by enhanced inflammation, proliferation, or chromatin remodeling • Tumor cell states correlate with unique immune-microenvironment features • Unique mutation and CNV profiles highlight potential genetic causes of heterogeneity Krull et al. analyzed bulk transcriptional, genomic, and immune profiles of B cells from follicular lymphoma and reveal 3 distinct transcriptional states. These cell states underscore the inherent variability of FL tumors, independent of stroma, and implicate intrinsic differences as an underpinning to FL heterogeneity.