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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 13 Issue 7 Pg. 1418-1431 (Nov 17 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 26549456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Histocompatibility Antigens Class II
• MHC class II transactivator protein
• Nuclear Proteins
• Trans-Activators

Topics

• Cell Line
• DNA Mutational Analysis
• Gene Expression
• Genetic Association Studies
• Genetic Predisposition to Disease
• Histocompatibility Antigens Class II (genetics, metabolism)
• Humans
• Introns
• Lymphoma, Large B-Cell, Diffuse (genetics, immunology, metabolism)
• Male
• Mediastinal Neoplasms (genetics, immunology, metabolism)
• Nuclear Proteins (genetics)
• Point Mutation
• Sequence Deletion
• Trans-Activators (genetics)
• Tumor Escape