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

By C. Steidl, Sohrab P. Shah, B. Woolcock, L. Rui, M. Kawahara, P. Farinha, N. Johnson, Yongjun Zhao, A. Telenius, Susana Ben Neriah and 17 more. Nature, 2011

612 citations recorded by the source corpus.

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 features. 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 cancers, whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity. 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.

Subfields: Immunology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/eb826aaf784f6a6081b04e51262272c5bc66673d

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Citations in the corpus

Constitutive AP-1 Activity and EBV Infection Induce PD-L1 in Hodgkin Lymphomas and Post-transplant Lymphoproliferative Disorders: Implications for Targeted Therapy (2012, background): “In cHL, the immunosuppressive microenvironment surrounding the malignant RS cells is suggestive of multiple immune evasionmechanisms (6, 9, 37, 38).”
Immune checkpoint blockade: a common denominator approach to cancer therapy (2015, background): “PD-L2, placing PD-1 ligands under the transcriptional control of the CIITA promoter, which is highly active in B cell lymphomas (Steidl et al., 2011).”
PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. (2016, neutral): “(%) Nodular sclerosis 93 (86) 25 (76) 39 (95) 29 (85) Mixed cellularity 12 (11) 8 (24) 1 (2) 3 (9) cHL, not otherwise specified 3 (3) — 1 (2) 2 (6)”
Cancer stem cells: an evolving concept (2012, background): “This facilitates their engraftment with human cells but also provides a system that lacks many elements that are now thought to substantially influence tumour growt”
The blockade of immune checkpoints in cancer immunotherapy (2012, background): “Upregulation of PDL2 on these lymphomas is commonly associated with gene amplification or rearrangement with the class II major histocompatibility complex (MHC) transactivator ( CIITA ) locus, which is highly transcriptionally active in B cell lymphoma”
The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. (2011, background): “sequencing technologies with the possibility of elucidating the whole genome sequence of large number of tumors at an affordable cost is the next step starting to produce early results.(101;126;127) The new technologies promise new insights into basic biology, allowing us to refine our clinical and ”
A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications (2020, background): “, 2019b) and inactivation of CIITA (Steidl et al., 2011) and HLA-DMB (Denzin and Cresswell, 1995), potentially modulating interactions between lymphoma cells and TFH cells.”
Analysis of the Coding Genome of Diffuse Large B-Cell Lymphoma (2011, background): “More recently, chromosomal translocations involving CIITA and amplifications or rearrangements of the genes encoding for the CD274 (also known as PDL1) and CD273 (also known as PDL2) ligands have been reported as recurrent events in PMBC”