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Cell Rep. 2015 Nov 17;13(7):1418-1431. doi: 10.1016/j.celrep.2015.10.008. Epub 2015 Nov 5.

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

Author information

1
Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
2
Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
3
Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Bioinformatics Training Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada.
4
Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
5
Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
6
Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: csteidl@bccancer.bc.ca.

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.

PMID:
26549456
DOI:
10.1016/j.celrep.2015.10.008
[Indexed for MEDLINE]
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