Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma
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 malignanc...
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| Format: | Journal Article |
| Language: | English |
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2019
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| Online Access: | https://hdl.handle.net/10356/89903 http://hdl.handle.net/10220/47777 |
| _version_ | 1811691875266985984 |
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| author | 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 |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) 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 |
| author_sort | Song, Tammy Linlin |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:26:50Z |
| format | Journal Article |
| id | ntu-10356/89903 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:26:50Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/899032020-03-07T12:57:25Z Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma 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 Lee Kong Chian School of Medicine (LKCMedicine) Anaplastic Lymphoma Kinase Ephrin Receptor A3 DRNTU::Science::Medicine 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. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) 2019-03-06T04:53:21Z 2019-12-06T17:36:15Z 2019-03-06T04:53:21Z 2019-12-06T17:36:15Z 2018 Journal Article 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 0006-4971 https://hdl.handle.net/10356/89903 http://hdl.handle.net/10220/47777 10.1182/blood-2018-01-829424 en Blood © 2018 The American Society of Hematology. All rights reserved. |
| spellingShingle | Anaplastic Lymphoma Kinase Ephrin Receptor A3 DRNTU::Science::Medicine 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 Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma |
| title | Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma |
| title_full | Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma |
| title_fullStr | Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma |
| title_full_unstemmed | Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma |
| title_short | Oncogenic activation of the stat3 pathway drives pd-l1 expression in natural killer/t-cell lymphoma |
| title_sort | oncogenic activation of the stat3 pathway drives pd l1 expression in natural killer t cell lymphoma |
| topic | Anaplastic Lymphoma Kinase Ephrin Receptor A3 DRNTU::Science::Medicine |
| url | https://hdl.handle.net/10356/89903 http://hdl.handle.net/10220/47777 |
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