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


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.

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Figure 1: CIITA BX648577 gene fusion observed using paired-end massively parallel whole transcriptome sequencing.
Figure 2: Molecular characterization of the gene fusion CIITA–BX648577 in Hodgkin lymphoma cell line KM-H2.
Figure 3: FISH on tissue microarrays showing recurrent CIITA break-apart in cHL and PMBCL.
Figure 4: CD274/CD273 expression on PMBCL cells inhibits T-cell activation.

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Gene Expression Omnibus

Data deposits

Array data are deposited in NCBI Gene Expression Omnibus under accession number GSE25990.


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This work is supported by a postdoctoral fellowship of the Cancer Research Society (Steven E. Drabin Fellowship) to C.S., the Michael Smith Foundation for Health Research to C.S. and S.P.S., the Lymphoma Research Foundation to C.S. and the Canadian Breast Cancer Foundation to S.P.S. Operational funds were available through the Canadian Institutes of Health Research, grant number 178536 to R.D.G. R.D.G., J.M.C., M.A.M. and D.E.H. are also supported by the Terry Fox Foundation (number 019001). This work was in part supported by an infrastructure grant of Genome Canada/Genome BC. U.S. is the recipient of a Howard Temin Award of the National Institutes of Health/National Cancer Institute (R00CA131503), a new investigator award of the Leukemia Research Foundation, and is the Diane and Arthur B. Belfer Faculty Scholar in Cancer Research of the Albert Einstein College of Medicine. We thank G. Simkin, C. Polumbo and T. Vogler for technical support. L.R. is the recipient of a CJ Martin Fellowship from the National Health and Medical Research Council of Australia.

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Authors and Affiliations



C.S. designed the research, performed FISH, PCR and direct sequencing, interpreted results and wrote the paper. S.P.S. designed the research, analysed the transcriptome data and wrote the paper. B.W.W. performed PCR and interpreted results. M.K., U.C.O. and L.R. performed in vitro functional analyses. P.F. reviewed pathology and constructed the tissue microarrays. N.A.J. performed single nucleotide polymorphism analyses. Y.Z. performed library construction and RNA-seq. A.T. performed nucleic acid extraction and quantitative RT-PCR. B.M. and S.B.N. performed FISH. A.M., M.S., G.L. and S.J.J. analysed the transcriptome data. A.D., A.B., L.R. and D.E.H. interpreted results. J.M.C. and K.J.S. provided clinical data. D.G.H. designed the research. L.M.S. and U.S. designed the research and interpreted results. M.A.A. designed the research. R.D.G. designed the research, constructed the tissue microarrays, interpreted results and wrote the paper.

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Correspondence to Randy D. Gascoyne.

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Steidl, C., Shah, S., Woolcock, B. et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471, 377–381 (2011).

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