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

Christian Steidl, Sohrab P. Shah, Bruce W. Woolcock, Lixin Rui, Masahiro Kawahara, Pedro Farinha, Nathalie A. Johnson, Yongjun Zhao, Adele Telenius, Susana Ben Neriah, Andrew McPherson, Barbara Meissner, Ujunwa C. Okoye, Arjan Diepstra, Anke Van Den Berg, Mark Sun, Gillian Leung, Steven J. Jones, Joseph M. Connors, David G. HuntsmanKerry J. Savage, Lisa M. Rimsza, Douglas E. Horsman, Louis M. Staudt, Ulrich Steidl, Marco A. Marra, Randy D. Gascoyne

Research output: Contribution to journalArticle

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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 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 receptorĝ€"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 tumourĝ€"microenvironment interactions across a spectrum of lymphoid cancers.

Original languageEnglish (US)
Pages (from-to)377-383
Number of pages7
JournalNature
Volume471
Issue number7338
DOIs
StatePublished - Mar 17 2011

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Gene Fusion
B-Cell Lymphoma
Major Histocompatibility Complex
Hodgkin Disease
Programmed Cell Death 1 Receptor
Neoplasms
Ligands
RNA Sequence Analysis
Genetic Translocation
Tumor Microenvironment
Transcriptome
Lymphoma
Down-Regulation
Cell Line
MHC class II transactivator protein
Genes

ASJC Scopus subject areas

  • General

Cite this

Steidl, C., Shah, S. P., Woolcock, B. W., Rui, L., Kawahara, M., Farinha, P., ... Gascoyne, R. D. (2011). MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature, 471(7338), 377-383. https://doi.org/10.1038/nature09754

MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. / Steidl, Christian; Shah, Sohrab P.; Woolcock, Bruce W.; Rui, Lixin; Kawahara, Masahiro; Farinha, Pedro; Johnson, Nathalie A.; Zhao, Yongjun; Telenius, Adele; Neriah, Susana Ben; McPherson, Andrew; Meissner, Barbara; Okoye, Ujunwa C.; Diepstra, Arjan; Van Den Berg, Anke; Sun, Mark; Leung, Gillian; Jones, Steven J.; Connors, Joseph M.; Huntsman, David G.; Savage, Kerry J.; Rimsza, Lisa M.; Horsman, Douglas E.; Staudt, Louis M.; Steidl, Ulrich; Marra, Marco A.; Gascoyne, Randy D.

In: Nature, Vol. 471, No. 7338, 17.03.2011, p. 377-383.

Research output: Contribution to journalArticle

Steidl, C, Shah, SP, Woolcock, BW, Rui, L, Kawahara, M, Farinha, P, Johnson, NA, Zhao, Y, Telenius, A, Neriah, SB, McPherson, A, Meissner, B, Okoye, UC, Diepstra, A, Van Den Berg, A, Sun, M, Leung, G, Jones, SJ, Connors, JM, Huntsman, DG, Savage, KJ, Rimsza, LM, Horsman, DE, Staudt, LM, Steidl, U, Marra, MA & Gascoyne, RD 2011, 'MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers', Nature, vol. 471, no. 7338, pp. 377-383. https://doi.org/10.1038/nature09754
Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature. 2011 Mar 17;471(7338):377-383. https://doi.org/10.1038/nature09754
Steidl, Christian ; Shah, Sohrab P. ; Woolcock, Bruce W. ; Rui, Lixin ; Kawahara, Masahiro ; Farinha, Pedro ; Johnson, Nathalie A. ; Zhao, Yongjun ; Telenius, Adele ; Neriah, Susana Ben ; McPherson, Andrew ; Meissner, Barbara ; Okoye, Ujunwa C. ; Diepstra, Arjan ; Van Den Berg, Anke ; Sun, Mark ; Leung, Gillian ; Jones, Steven J. ; Connors, Joseph M. ; Huntsman, David G. ; Savage, Kerry J. ; Rimsza, Lisa M. ; Horsman, Douglas E. ; Staudt, Louis M. ; Steidl, Ulrich ; Marra, Marco A. ; Gascoyne, Randy D. / MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. In: Nature. 2011 ; Vol. 471, No. 7338. pp. 377-383.
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AU - Shah, Sohrab P.

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AU - Kawahara, Masahiro

AU - Farinha, Pedro

AU - Johnson, Nathalie A.

AU - Zhao, Yongjun

AU - Telenius, Adele

AU - Neriah, Susana Ben

AU - McPherson, Andrew

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AU - Huntsman, David G.

AU - Savage, Kerry J.

AU - Rimsza, Lisa M.

AU - Horsman, Douglas E.

AU - Staudt, Louis M.

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