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

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, CREBBP mutations 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. CREBBP mutant 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 implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.This work was supported by grants from the Lymphoma Research Foundation (A.A.A.), the Leukemia and Lymphoma Society (Specialized Center of Research Excellence Program), the NIH (S10 RR02933801, R01 CA151748), the Albert and Mary Yu Gift Fund, and the Evelyn Leung Gift Fund. Research in the I.S.-G. group is supported partially by Federacion Espanola de Enfermedades Raras (FEDER) and The Ministerio de Ciencia e Innovacion (MICINN) (SAF2009-0883 and SAF2012-32810). M.R.G. is a Special Fellow of the Leukemia and Lymphoma Society. R.L. is an American Cancer Society Clinical Research Professor. A.A.A. is a Doris Duke Charitable Foundation Clinical Investigator.Peer Reviewe