Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (10), p.E1116-E1125
• Main Authors: Green, Michael R., Kihira, Shingo, Liu, Chih Long, Nair, Ramesh V., Salari, Raheleh, Gentles, Andrew J., Irish, Jonathan, Stehr, Henning, Vicente-Dueñas, Carolina, Romero-Camarero, Isabel, Sanchez-Garcia, Isidro, Plevritis, Sylvia K., Arber, Daniel A., Batzoglou, Serafim, Levy, Ronald, Alizadeh, Ash A.
• Format: Article
• Language: English
• Subjects: Antigen-Presenting Cells - immunology; Antigens; Biological Sciences; Chromatin; Chromatin - metabolism; CREB-Binding Protein - genetics; Evolution; Flow Cytometry; Histocompatibility Antigens Class II - genetics; Humans; Leukemia; Lymphoma; Lymphoma, Follicular - genetics; Lymphoma, Follicular - immunology; Mutation; Neoplastic Stem Cells - pathology; PNAS Plus; Polymerase Chain Reaction; T cell receptors; Translocation; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1501199112

Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes,CREBBPmutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes.CREBBPmutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicateCREBBPmutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.