Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression

Anja Mottok, Bruce Woolcock, Fong Chun Chan, King Mong Tong, Lauren Chong, Pedro Farinha, Adèle Telenius, Elizabeth Chavez, Suvan Ramchandani, Marie Drake, Merrill Boyle, Susana Ben-Neriah, David W. Scott, Lisa M Rimsza, Reiner Siebert, Randy D. Gascoyne, Christian Steidl

Research output: Contribution to journalArticle

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Abstract

Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive non-Hodgkin's lymphoma, predominantly affecting young patients. We analyzed 45 primary PMBCL tumor biopsies and 3 PMBCL-derived cell lines for the presence of genetic alterations involving the major histocompatibility complex (MHC) class II transactivator CIITA and found frequent aberrations consisting of structural genomic rearrangements, missense, nonsense, and frame-shift mutations (53% of primary tumor biopsies and all cell lines). We also detected intron 1 mutations in 47% of the cases, and detailed sequence analysis strongly suggests AID-mediated aberrant somatic hypermutation as the mutational mechanism. Furthermore, we demonstrate that genomic lesions in CIITA result in decreased protein expression and reduction of MHC class II surface expression, creating an immune privilege phenotype in PMBCL. In summary, we establish CIITA alterations as a common mechanism of immune escape through reduction of MHC class II expression in PMBCL, with potential implications for future treatments targeting microenvironment-related biology.

Original languageEnglish (US)
Pages (from-to)1418-1431
Number of pages14
JournalCell Reports
Volume13
Issue number7
DOIs
StatePublished - Nov 17 2015

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B-Cell Lymphoma
Major Histocompatibility Complex
Biopsy
Cells
Tumors
Aberrations
Introns
Cell Line
Frameshift Mutation
Non-Hodgkin's Lymphoma
Sequence Analysis
Neoplasms
Proteins
Phenotype
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. / Mottok, Anja; Woolcock, Bruce; Chan, Fong Chun; Tong, King Mong; Chong, Lauren; Farinha, Pedro; Telenius, Adèle; Chavez, Elizabeth; Ramchandani, Suvan; Drake, Marie; Boyle, Merrill; Ben-Neriah, Susana; Scott, David W.; Rimsza, Lisa M; Siebert, Reiner; Gascoyne, Randy D.; Steidl, Christian.

In: Cell Reports, Vol. 13, No. 7, 17.11.2015, p. 1418-1431.

Research output: Contribution to journalArticle

Mottok, A, Woolcock, B, Chan, FC, Tong, KM, Chong, L, Farinha, P, Telenius, A, Chavez, E, Ramchandani, S, Drake, M, Boyle, M, Ben-Neriah, S, Scott, DW, Rimsza, LM, Siebert, R, Gascoyne, RD & Steidl, C 2015, 'Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression', Cell Reports, vol. 13, no. 7, pp. 1418-1431. https://doi.org/10.1016/j.celrep.2015.10.008
Mottok, Anja ; Woolcock, Bruce ; Chan, Fong Chun ; Tong, King Mong ; Chong, Lauren ; Farinha, Pedro ; Telenius, Adèle ; Chavez, Elizabeth ; Ramchandani, Suvan ; Drake, Marie ; Boyle, Merrill ; Ben-Neriah, Susana ; Scott, David W. ; Rimsza, Lisa M ; Siebert, Reiner ; Gascoyne, Randy D. ; Steidl, Christian. / Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. In: Cell Reports. 2015 ; Vol. 13, No. 7. pp. 1418-1431.
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