title: Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma.
abstract: CTLA4 and CD28 are co-regulatory receptors with opposite roles in T-cell signaling. By RNA sequencing, we identified a fusion between the two genes from partial gene duplication in a case of angioimmunoblastic T-cell lymphoma. The fusion gene, which codes for the extracellular domain of CTLA4 and the cytoplasmic region of CD28, is likely capable of transforming inhibitory signals into stimulatory signals for T-cell activation. Ectopic expression of the fusion transcript in Jurkat and H9 cells resulted in enhanced proliferation and AKT and ERK phosphorylation, indicating activation of downstream oncogenic pathways. To estimate the frequency of this gene fusion in mature T-cell lymphomas, we examined 115 T-cell lymphoma samples of diverse subtypes using reverse transcriptase polymerase chain reaction analysis and Sanger sequencing. We identified the fusion in 26 of 45 cases of angioimmunoblastic T-cell lymphomas (58%), nine of 39 peripheral T-cell lymphomas, not otherwise specified (23%), and nine of 31 extranodal NK/T cell lymphomas (29%). We further investigated the mutation status of 70 lymphoma-associated genes using ultra-deep targeted resequencing for 74 mature T-cell lymphoma samples. The mutational landscape we obtained suggests that T-cell lymphoma results from diverse combinations of multiple gene mutations. The CTLA4-CD28 gene fusion is likely a major contributor to the pathogenesis of T-cell lymphomas and represents a potential target for anti-CTLA4 cancer immunotherapy.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Ewha Womans University, Seoul, Korea.
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Yoo
authors.affiliation: Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea.
authors.forename: Pora
authors.initials: P
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Ewha Womans University, Seoul, Korea Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea Department of Bio-Information Science, Ewha Womans University, Ewha Womans University, Seoul, Korea.
authors.forename: Sangok
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kang
authors.affiliation: DNA Link Inc., Ewha Womans University, Seoul, Korea.
authors.forename: Hye Yoon
authors.initials: HY
authors.lastname: Jang
authors.affiliation: DNA Link Inc., Ewha Womans University, Seoul, Korea.
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Korea.
authors.forename: Jaesang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Ewha Womans University, Seoul, Korea Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Samsung Biomedical Research Institute, Research Institute for Future Medicine, Samsung Medical Center, Ewha Womans University, Seoul, Korea Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ewha Womans University, Seoul, Korea yhko310@skku.edu sanghyuk@ewha.ac.kr.
authors.forename: Young Hyeh
authors.initials: YH
authors.lastname: Ko
authors.affiliation: Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University, Seoul, Korea Department of Bio-Information Science, Ewha Womans University, Ewha Womans University, Seoul, Korea Department of Life Science, Ewha Womans University, Seoul, Korea yhko310@skku.edu sanghyuk@ewha.ac.kr.
authors.forename: Sanghyuk
authors.initials: S
authors.lastname: Lee
mesh_terms: D018106:CD28 Antigens / Q000235:genetics*; D060908:CTLA-4 Antigen / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D018628:Gene Dosage; D020869:Gene Expression Profiling; D023061:Gene Order; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D015203:Reproducibility of Results
chemical_list: D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D016207:Cytokines; D015514:Oncogene Proteins, Fusion
references.citation: Nature. 2012 Oct 4;490(7418):116-20
references.pmid: 22885699
references.citation: Blood. 2015 Jan 22;125(4):658-67
references.pmid: 25452615
references.citation: Immunol Rev. 2009 May;229(1):12-26
references.pmid: 19426212
references.citation: Mol Genet Genomic Med. 2015 Mar;3(2):130-6
references.pmid: 25802883
references.citation: N Engl J Med. 2014 Dec 25;371(26):2477-87
references.pmid: 25426838
references.citation: Nat Genet. 2014 Apr;46(4):329-35
references.pmid: 24531327
references.citation: Nat Genet. 2004 Oct;36(10):1084-9
references.pmid: 15361874
references.citation: Nat Genet. 2014 Feb;46(2):171-5
references.pmid: 24413737
references.citation: Science. 1996 Mar 22;271(5256):1734-6
references.pmid: 8596936
references.citation: Blood. 2012 Aug 16;120(7):1466-9
references.pmid: 22760778
references.citation: Nat Genet. 2012 Dec;44(12):1316-20
references.pmid: 23143595
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3879-84
references.pmid: 22343534
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Blood. 2012 Feb 23;119(8):1901-3
references.pmid: 22215888
references.citation: Nat Genet. 2014 Feb;46(2):176-81
references.pmid: 24362818
references.citation: Haematologica. 2015 Dec;100(12):e505-7
references.pmid: 26405154
references.citation: Nat Genet. 2014 Feb;46(2):166-70
references.pmid: 24413734
references.citation: Nat Med. 2014 Dec;20(12):1472-8
references.pmid: 25326804
references.citation: Blood. 2012 Jun 14;119(24):5678-87
references.pmid: 22538857
references.citation: N Engl J Med. 2012 Jan 5;366(1):95-6
references.pmid: 22216861
references.citation: Science. 2014 Sep 26;345(6204):1623-7
references.pmid: 25213377
references.citation: Nat Genet. 2014 Apr;46(4):371-5
references.pmid: 24584070
references.citation: Nat Genet. 2012 Dec;44(12):1321-5
references.pmid: 23143597
references.citation: N Engl J Med. 2014 Dec 25;371(26):2488-98
references.pmid: 25426837
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1398-403
references.pmid: 23292937
references.citation: Blood. 2009 Jul 16;114(3):535-46
references.pmid: 19451549
references.citation: Nat Genet. 2015 Sep;47(9):1056-60
references.pmid: 26258847