Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma

Chi Young Ok, Jiayu Chen, Zijun Y Xu-Monette, Alexandar Tzankov, Ganiraju C Manyam, Ling Li, Carlo Visco, Santiago Montes-Moreno, Karen Dybkær, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L Richards, Eric D Hsi, William W L Choi, J Han van Krieken, Jooryung Huh, Xiaoying Zhao, Maurilio Ponzoni & 8 andre Andrés J M Ferreri, Francesco Bertoni, John P Farnen, Michael B Møller, Miguel A Piris, Jane N Winter, L Jeffrey Medeiros, Ken H Young

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

PURPOSE: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited.

EXPERIMENTAL DESIGN: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations.

RESULTS: pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK-STAT pathway to be enriched in pSTAT3(+) DLBCL.

CONCLUSIONS: The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL. Clin Cancer Res; 20(19); 5113-23. ©2014 AACR.

OriginalsprogEngelsk
TidsskriftClinical Cancer Research
Vol/bind20
Udgave nummer19
Sider (fra-til)5113-23
ISSN1078-0432
DOI
StatusUdgivet - 2014

Fingeraftryk

Lymphoma, Large B-Cell, Diffuse
Gene Expression Profiling
Disease-Free Survival
Lymphoma
Neoplasms
Up-Regulation
Multivariate Analysis
Cell Proliferation
Clinical Trials
Growth

Citer dette

Ok, C. Y., Chen, J., Xu-Monette, Z. Y., Tzankov, A., Manyam, G. C., Li, L., ... Young, K. H. (2014). Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma. Clinical Cancer Research, 20(19), 5113-23. https://doi.org/10.1158/1078-0432.CCR-14-0683
Ok, Chi Young ; Chen, Jiayu ; Xu-Monette, Zijun Y ; Tzankov, Alexandar ; Manyam, Ganiraju C ; Li, Ling ; Visco, Carlo ; Montes-Moreno, Santiago ; Dybkær, Karen ; Chiu, April ; Orazi, Attilio ; Zu, Youli ; Bhagat, Govind ; Richards, Kristy L ; Hsi, Eric D ; Choi, William W L ; van Krieken, J Han ; Huh, Jooryung ; Zhao, Xiaoying ; Ponzoni, Maurilio ; Ferreri, Andrés J M ; Bertoni, Francesco ; Farnen, John P ; Møller, Michael B ; Piris, Miguel A ; Winter, Jane N ; Medeiros, L Jeffrey ; Young, Ken H. / Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma. I: Clinical Cancer Research. 2014 ; Bind 20, Nr. 19. s. 5113-23.
@article{b9a5767887384fb9ba1373c2a299c3fc,
title = "Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma",
abstract = "PURPOSE: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited.EXPERIMENTAL DESIGN: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations.RESULTS: pSTAT3 expression was observed in 16{\%} of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK-STAT pathway to be enriched in pSTAT3(+) DLBCL.CONCLUSIONS: The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL. Clin Cancer Res; 20(19); 5113-23. {\circledC}2014 AACR.",
author = "Ok, {Chi Young} and Jiayu Chen and Xu-Monette, {Zijun Y} and Alexandar Tzankov and Manyam, {Ganiraju C} and Ling Li and Carlo Visco and Santiago Montes-Moreno and Karen Dybk{\ae}r and April Chiu and Attilio Orazi and Youli Zu and Govind Bhagat and Richards, {Kristy L} and Hsi, {Eric D} and Choi, {William W L} and {van Krieken}, {J Han} and Jooryung Huh and Xiaoying Zhao and Maurilio Ponzoni and Ferreri, {Andr{\'e}s J M} and Francesco Bertoni and Farnen, {John P} and M{\o}ller, {Michael B} and Piris, {Miguel A} and Winter, {Jane N} and Medeiros, {L Jeffrey} and Young, {Ken H}",
note = "{\circledC}2014 American Association for Cancer Research.",
year = "2014",
doi = "10.1158/1078-0432.CCR-14-0683",
language = "English",
volume = "20",
pages = "5113--23",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research (A A C R)",
number = "19",

}

Ok, CY, Chen, J, Xu-Monette, ZY, Tzankov, A, Manyam, GC, Li, L, Visco, C, Montes-Moreno, S, Dybkær, K, Chiu, A, Orazi, A, Zu, Y, Bhagat, G, Richards, KL, Hsi, ED, Choi, WWL, van Krieken, JH, Huh, J, Zhao, X, Ponzoni, M, Ferreri, AJM, Bertoni, F, Farnen, JP, Møller, MB, Piris, MA, Winter, JN, Medeiros, LJ & Young, KH 2014, 'Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma', Clinical Cancer Research, bind 20, nr. 19, s. 5113-23. https://doi.org/10.1158/1078-0432.CCR-14-0683

Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma. / Ok, Chi Young; Chen, Jiayu; Xu-Monette, Zijun Y; Tzankov, Alexandar; Manyam, Ganiraju C; Li, Ling; Visco, Carlo; Montes-Moreno, Santiago; Dybkær, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L; Hsi, Eric D; Choi, William W L; van Krieken, J Han; Huh, Jooryung; Zhao, Xiaoying; Ponzoni, Maurilio; Ferreri, Andrés J M; Bertoni, Francesco; Farnen, John P; Møller, Michael B; Piris, Miguel A; Winter, Jane N; Medeiros, L Jeffrey; Young, Ken H.

I: Clinical Cancer Research, Bind 20, Nr. 19, 2014, s. 5113-23.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Clinical Implications of Phosphorylated STAT3 Expression in De Novo Diffuse Large B-cell Lymphoma

AU - Ok, Chi Young

AU - Chen, Jiayu

AU - Xu-Monette, Zijun Y

AU - Tzankov, Alexandar

AU - Manyam, Ganiraju C

AU - Li, Ling

AU - Visco, Carlo

AU - Montes-Moreno, Santiago

AU - Dybkær, Karen

AU - Chiu, April

AU - Orazi, Attilio

AU - Zu, Youli

AU - Bhagat, Govind

AU - Richards, Kristy L

AU - Hsi, Eric D

AU - Choi, William W L

AU - van Krieken, J Han

AU - Huh, Jooryung

AU - Zhao, Xiaoying

AU - Ponzoni, Maurilio

AU - Ferreri, Andrés J M

AU - Bertoni, Francesco

AU - Farnen, John P

AU - Møller, Michael B

AU - Piris, Miguel A

AU - Winter, Jane N

AU - Medeiros, L Jeffrey

AU - Young, Ken H

N1 - ©2014 American Association for Cancer Research.

PY - 2014

Y1 - 2014

N2 - PURPOSE: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited.EXPERIMENTAL DESIGN: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations.RESULTS: pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK-STAT pathway to be enriched in pSTAT3(+) DLBCL.CONCLUSIONS: The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL. Clin Cancer Res; 20(19); 5113-23. ©2014 AACR.

AB - PURPOSE: Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited.EXPERIMENTAL DESIGN: We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations.RESULTS: pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK-STAT pathway to be enriched in pSTAT3(+) DLBCL.CONCLUSIONS: The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL. Clin Cancer Res; 20(19); 5113-23. ©2014 AACR.

U2 - 10.1158/1078-0432.CCR-14-0683

DO - 10.1158/1078-0432.CCR-14-0683

M3 - Journal article

VL - 20

SP - 5113

EP - 5123

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 19

ER -