Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/89903
Title: Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma
Authors: Song, Tammy Linlin
Nairismägi, Maarja-Liisa
Laurensia, Yurike
Lim, Jing-Quan
Tan, Jing
Li, Zhi-Mei
Pang, Wan-Lu
Kizhakeyil, Atish
Wijaya, Giovani-Claresta
Huang, Da-Chuan
Nagarajan, Sanjanaa
Chia, Burton Kuan-Hui
Cheah, Daryl
Liu, Yan-Hui
Zhang, Fen
Rao, Hui-Lan
Tang, Tiffany
Wong, Esther Kam-Yin
Bei, Jin-Xin
Iqbal, Jabed
Grigoropoulos, Nicholas-Francis
Ng, Siok-Bian
Chng, Wee-Joo
Teh, Bin-Tean
Tan, Soo-Yong
Verma, Navin Kumar
Fan, Hao
Lim, Soon-Thye
Ong, Choon-Kiat
Keywords: Anaplastic Lymphoma Kinase
Ephrin Receptor A3
DRNTU::Science::Medicine
Issue Date: 2018
Source: Song, 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-2018-01-829424
Series/Report no.: Blood
Abstract: Mature 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.
URI: https://hdl.handle.net/10356/89903
http://hdl.handle.net/10220/47777
ISSN: 0006-4971
DOI: 10.1182/blood-2018-01-829424
Rights: © 2018 The American Society of Hematology. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:LKCMedicine Journal Articles

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.