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Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):E1116-25. doi: 10.1073/pnas.1501199112. Epub 2015 Feb 23.

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

Author information

  • 1Division of Oncology, Center for Cancer Systems Biology, arasha@stanford.edu michael.green@unmc.edu.
  • 2Division of Oncology.
  • 3Division of Oncology, Division of Radiology.
  • 4Department of Computer Science, and.
  • 5Center for Cancer Systems Biology, Division of Radiology.
  • 6Stanford Cancer Institute, Department of Medicine, Stanford University, Stanford, CA 94305;
  • 7Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Campus M. de Unamuno s/n, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Salamanca 37007, Spain; Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain; and.
  • 8Department of Pathology, Stanford University, Stanford, CA 94305.
  • 9Division of Oncology, Center for Cancer Systems Biology, Stanford Cancer Institute, Department of Medicine, Stanford University, Stanford, CA 94305;
  • 10Division of Oncology, Center for Cancer Systems Biology, Stanford Cancer Institute, Department of Medicine, Stanford University, Stanford, CA 94305; arasha@stanford.edu michael.green@unmc.edu.

Abstract

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.

KEYWORDS:

CREBBP; antigen presentation; exome; hierarchy; lymphoma

PMID:
25713363
[PubMed - indexed for MEDLINE]
PMCID:
PMC4364211
Free PMC Article
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