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

• DOI: 10.1016/j.xcrm.2024.101443
• Publication Date: 2024-02-29T15:27:56Z
• Authors: Jordan E. Krull; Kerstin Wenzl; Melissa A. Hopper; Michelle K. Manske; Vivekananda Sarangi; Matthew J. Maurer; Melissa C. Larson; Patrizia Mondello; ZhiZhang Yang; Joseph P. Novak; Makayla Serres; Kaitlyn R. Whitaker; Jose C. Villasboa...; Thomas M. Habermann; Thomas E. Witzig; Brian K. Link; Lisa M. Rimsza; Rebecca L. King; Stephen M. Ansell; James R. Cerhan; Anne J. Novak
• Keywords: B cell; follicular lymphoma; genomics; germinal center; transcriptome; tumor microenvironment; B-Lymphocytes; Lymphoma, B-Cell; Tumor Microenvironment; Humans; Lymphoma, Follicular; Article; Chromatin

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.