MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers

Abstract

Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features1,2. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq). Here we show a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA (MHC2TA) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of various in-frame gene fusions, and we report that CIITA gene alterations impact survival in primary mediastinal B-cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These receptor–ligand interactions have been shown to impact anti-tumour immune responses in several cancers3, whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity4. Thus, our findings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumour–microenvironment interactions across a spectrum of lymphoid cancers.

RNA-Seq and human complex diseases: recent accomplishments and future perspectives

“…[56][57][58] Most of them have discovered a considerable fraction of fusion transcripts -that is chimeric mRNAs that may alter cell's functionality -commonly produced by genomes rearrangement and critically involved in the pathogenesis of several types of malignancies. However, it should be noted that some of the newly identified rearrangements may not be the molecular cause of the aberrant phenotypes, and that using RNA-Seq solely allows detecting expressed fusion genes giving no information about other kind of structural rearrangements.…”

“…In a recent study on B-cell lymphomas, MHC class II transactivator (CIITA) has been identified as a novel partner of various fusions transcripts, suggesting a possible novel intriguing genetic mechanism underlying the onset of lymphoid cancers. 58 Moreover, the application of RNA-Seq to breast cancer samples has allowed to detect alternative splicing events associated with epithelialmesenchymal transition (EMT), suggesting the classification of cancer cell lines into basal and luminal subtypes, based on their EMT-associated splicing pattern. 62 Furthermore, the integration of multiple levels of analysis has allowed the identification of fusion genes associated with CNVs, suggesting that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions, or may mediate the activation of a dormant gene.…”

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

“…46,47 These structural alterations appear to occur at a low frequency, although this might be underestimated due to the heterogeneity of clinical samples. Mutations in the HLA class II-regulatory gene RFX5 were found at frequency of about 30% of HLA class II antigen-negative microsatellite-unstable (MSI-H) CRC (28.9%), while CIITA mutations were only found in about 5% of these lesions.…”

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

“…30 However, MHC II is shown to be downregulated in a subset of classical Hodgkin lymphoma cases, 32 partly owing to translocations involving the MHC II transactivator (CIITA). 33 Decreased MHC class II expression has been linked to reduced tumor cell immunogenicity. A strong expression of STAT3 was observed in Hodgkin and Reed-Sternberg cells in the present and previous studies.…”