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

Michael R. Green, Shingo Kihira, Chih Long Liu, Ramesh V. Nair, Raheleh Salari, Andrew J. Gentles, Jonathan Irish, Henning Stehr, Carolina Vicente-Dueñas, Isabel Romero-Camarero, Isidro Sanchez-Garcia, Sylvia K. Plevritis, Daniel A. Arber, Serafim Batzoglou, Ronald Levy, Ash A. Alizadeh

Research output: Contribution to journalArticle

121 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E1116-E1125
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number10
DOIs
StatePublished - Mar 10 2015

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Follicular Lymphoma
Antigen Presentation
Mutation
Neoplasms
B-Lymphocytes
T-Lymphocytes
Genes
Chromatin
Modifier Genes
B-Cell Leukemia
Immune Evasion
B-Cell Lymphoma
Helper-Inducer T-Lymphocytes
Transcriptional Activation
Genome
Biopsy
Recurrence
Cell Line

Keywords

  • Antigen presentation
  • CREBBP
  • Exome
  • Hierarchy
  • Lymphoma

ASJC Scopus subject areas

  • General

Cite this

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 10, 10.03.2015, p. E1116-E1125.

Research output: Contribution to journalArticle

Green, MR, Kihira, S, Liu, CL, Nair, RV, Salari, R, Gentles, AJ, Irish, J, Stehr, H, Vicente-Dueñas, C, Romero-Camarero, I, Sanchez-Garcia, I, Plevritis, SK, Arber, DA, Batzoglou, S, Levy, R & Alizadeh, AA 2015, 'Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 10, pp. E1116-E1125. https://doi.org/10.1073/pnas.1501199112
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. / Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 10. pp. E1116-E1125.
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N2 - 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.

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