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Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma

Title
Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma
Authors
Yoo, Hae YongKim, PoraKim, Won SeogLee, Seung HoKim, SangokKang, So YoungJang, Hye YoonLee, Jong-EunKim, JaesangKim, Seok JinKo, Young HyehLee, Sanghyuk
Ewha Authors
이상혁김재상
SCOPUS Author ID
이상혁scopus; 김재상scopus
Issue Date
2016
Journal Title
HAEMATOLOGICA
ISSN
0390-6078JCR Link
Citation
vol. 101, no. 6, pp. 757 - 763
Publisher
FERRATA STORTI FOUNDATION
Indexed
SCI; SCIE; SCOPUS WOS scopus
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.
DOI
10.3324/haematol.2015.139253
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자연과학대학 > 생명과학전공 > Journal papers
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