@article{b8a77ab8f8c64e6d96a41d472e9eac8f,
title = "Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression",
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.",
author = "Anja Mottok and Bruce Woolcock and Chan, {Fong Chun} and Tong, {King Mong} and Lauren Chong and Pedro Farinha and Ad{\`e}le Telenius and Elizabeth Chavez and Suvan Ramchandani and Marie Drake and Merrill Boyle and Susana Ben-Neriah and Scott, {David W.} and Rimsza, {Lisa M.} and Reiner Siebert and Gascoyne, {Randy D.} and Christian Steidl",
note = "Funding Information: This work is supported by funds from the Canadian Institutes of Health Research to R.D.G. and C.S. (#178536) and a Terry Fox Research Institute team grant (#1023) to C.S. A.M. is supported by a postdoctoral fellowship award from the Mildred-Scheel-Cancer Foundation (D/12/03754). C.S. is the recipient of a Career Investigator Scholarship award from the Michael Smith Foundation for Health Research (#5120). R.S. is supported by the KinderKrebsInitiative Buchholz/Holm-Seppensen. We would like to thank A. Lipski, A. Jenks, the Centre for Translational and Applied Genomics (CTAG), and C. Becher (Institute of Human Genetics, Kiel, Germany) for excellent technical support. Publisher Copyright: {\textcopyright} 2015 The Authors. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.",
year = "2015",
month = nov,
day = "17",
doi = "10.1016/j.celrep.2015.10.008",
language = "English (US)",
volume = "13",
pages = "1418--1431",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}