期刊
CELL REPORTS
卷 13, 期 7, 页码 1418-1431出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.10.008
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资金
- Canadian Institutes of Health Research [178536]
- Terry Fox Research Institute [1023]
- Mildred-Scheel-Cancer Foundation [D/12/03754]
- Michael Smith Foundation for Health Research [5120]
- KinderKrebsInitiative Buchholz/Holm-Seppensen
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 frameshift 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.
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