dc.contributor.authorSong, Tammy Linlin
dc.contributor.authorNairismägi, Maarja-Liisa
dc.contributor.authorLaurensia, Yurike
dc.contributor.authorLim, Jing-Quan
dc.contributor.authorTan, Jing
dc.contributor.authorLi, Zhi-Mei
dc.contributor.authorPang, Wan-Lu
dc.contributor.authorKizhakeyil, Atish
dc.contributor.authorWijaya, Giovani-Claresta
dc.contributor.authorHuang, Da-Chuan
dc.contributor.authorNagarajan, Sanjanaa
dc.contributor.authorChia, Burton Kuan-Hui
dc.contributor.authorCheah, Daryl
dc.contributor.authorLiu, Yan-Hui
dc.contributor.authorZhang, Fen
dc.contributor.authorRao, Hui-Lan
dc.contributor.authorTang, Tiffany
dc.contributor.authorWong, Esther Kam-Yin
dc.contributor.authorBei, Jin-Xin
dc.contributor.authorIqbal, Jabed
dc.contributor.authorGrigoropoulos, Nicholas-Francis
dc.contributor.authorNg, Siok-Bian
dc.contributor.authorChng, Wee-Joo
dc.contributor.authorTeh, Bin-Tean
dc.contributor.authorTan, Soo-Yong
dc.contributor.authorVerma, Navin Kumar
dc.contributor.authorFan, Hao
dc.contributor.authorLim, Soon-Thye
dc.contributor.authorOng, Choon-Kiat
dc.date.accessioned2019-03-06T04:53:21Z
dc.date.available2019-03-06T04:53:21Z
dc.date.issued2018
dc.identifier.citationSong, T. L., Nairismägi, M.-L., Laurensia, Y., Lim, J-Q., Tan, J., Li, Z-M., . . . Ong, C-K. (2018). Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma. Blood, 132(11), 1146-1158. doi:10.1182/blood-2018-01-829424en_US
dc.identifier.issn0006-4971en_US
dc.identifier.urihttp://hdl.handle.net/10220/47777
dc.description.abstractMature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL.en_US
dc.description.sponsorshipASTAR (Agency for Sci., Tech. and Research, S’pore)en_US
dc.description.sponsorshipNMRC (Natl Medical Research Council, S’pore)en_US
dc.description.sponsorshipMOH (Min. of Health, S’pore)en_US
dc.language.isoenen_US
dc.relation.ispartofseriesBlooden_US
dc.rights© 2018 The American Society of Hematology. All rights reserved.en_US
dc.subjectAnaplastic Lymphoma Kinaseen_US
dc.subjectEphrin Receptor A3en_US
dc.subjectDRNTU::Science::Medicineen_US
dc.titleOncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphomaen_US
dc.typeJournal Article
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en_US
dc.identifier.doihttp://dx.doi.org/10.1182/blood-2018-01-829424


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