Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP

Xin Huang, Bin Meng, Javeed Iqbal, B. Belinda Ding, Anamarija M. Perry, Wenfeng Cao, Lynette M Smith, Chengfeng Bi, Chunsun Jiang, Timothy Charles Greiner, Dennis D. Weisenburger, Lisa Rimsza, Andreas Rosenwald, German Ott, Jan Delabie, Elias Campo, Rita M. Braziel, Randy D. Gascoyne, James R. Cook, Raymond R. TubbsElaine S. Jaffe, James Olen Armitage, Julie Marie Vose, Louis M. Staudt, Timothy W. McKeithan, Wing C. Chan, B. Hilda Ye, Kai Fu

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Abstract

Purpose We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. Patients and Methods By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. Results PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P < .025). Conclusion STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.

Original languageEnglish (US)
Pages (from-to)4520-4528
Number of pages9
JournalJournal of Clinical Oncology
Volume31
Issue number36
DOIs
StatePublished - Dec 30 2013

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Phosphotyrosine
Lymphoma, Large B-Cell, Diffuse
B-Lymphocytes
Survival
Messenger RNA
Vincristine
Prednisone
Doxorubicin
Cyclophosphamide
Small Interfering RNA
Transcriptional Activation
Disease-Free Survival
Cell Line
Genes
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP. / Huang, Xin; Meng, Bin; Iqbal, Javeed; Ding, B. Belinda; Perry, Anamarija M.; Cao, Wenfeng; Smith, Lynette M; Bi, Chengfeng; Jiang, Chunsun; Greiner, Timothy Charles; Weisenburger, Dennis D.; Rimsza, Lisa; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M.; Gascoyne, Randy D.; Cook, James R.; Tubbs, Raymond R.; Jaffe, Elaine S.; Armitage, James Olen; Vose, Julie Marie; Staudt, Louis M.; McKeithan, Timothy W.; Chan, Wing C.; Ye, B. Hilda; Fu, Kai.

In: Journal of Clinical Oncology, Vol. 31, No. 36, 30.12.2013, p. 4520-4528.

Research output: Contribution to journalArticle

Huang, X, Meng, B, Iqbal, J, Ding, BB, Perry, AM, Cao, W, Smith, LM, Bi, C, Jiang, C, Greiner, TC, Weisenburger, DD, Rimsza, L, Rosenwald, A, Ott, G, Delabie, J, Campo, E, Braziel, RM, Gascoyne, RD, Cook, JR, Tubbs, RR, Jaffe, ES, Armitage, JO, Vose, JM, Staudt, LM, McKeithan, TW, Chan, WC, Ye, BH & Fu, K 2013, 'Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP', Journal of Clinical Oncology, vol. 31, no. 36, pp. 4520-4528. https://doi.org/10.1200/JCO.2012.45.6004
Huang, Xin ; Meng, Bin ; Iqbal, Javeed ; Ding, B. Belinda ; Perry, Anamarija M. ; Cao, Wenfeng ; Smith, Lynette M ; Bi, Chengfeng ; Jiang, Chunsun ; Greiner, Timothy Charles ; Weisenburger, Dennis D. ; Rimsza, Lisa ; Rosenwald, Andreas ; Ott, German ; Delabie, Jan ; Campo, Elias ; Braziel, Rita M. ; Gascoyne, Randy D. ; Cook, James R. ; Tubbs, Raymond R. ; Jaffe, Elaine S. ; Armitage, James Olen ; Vose, Julie Marie ; Staudt, Louis M. ; McKeithan, Timothy W. ; Chan, Wing C. ; Ye, B. Hilda ; Fu, Kai. / Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP. In: Journal of Clinical Oncology. 2013 ; Vol. 31, No. 36. pp. 4520-4528.
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title = "Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP",
abstract = "Purpose We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. Patients and Methods By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. Results PY-STAT3 was detected in 37{\%} of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P < .025). Conclusion STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.",
author = "Xin Huang and Bin Meng and Javeed Iqbal and Ding, {B. Belinda} and Perry, {Anamarija M.} and Wenfeng Cao and Smith, {Lynette M} and Chengfeng Bi and Chunsun Jiang and Greiner, {Timothy Charles} and Weisenburger, {Dennis D.} and Lisa Rimsza and Andreas Rosenwald and German Ott and Jan Delabie and Elias Campo and Braziel, {Rita M.} and Gascoyne, {Randy D.} and Cook, {James R.} and Tubbs, {Raymond R.} and Jaffe, {Elaine S.} and Armitage, {James Olen} and Vose, {Julie Marie} and Staudt, {Louis M.} and McKeithan, {Timothy W.} and Chan, {Wing C.} and Ye, {B. Hilda} and Kai Fu",
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TY - JOUR

T1 - Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma treated with R-CHOP

AU - Huang, Xin

AU - Meng, Bin

AU - Iqbal, Javeed

AU - Ding, B. Belinda

AU - Perry, Anamarija M.

AU - Cao, Wenfeng

AU - Smith, Lynette M

AU - Bi, Chengfeng

AU - Jiang, Chunsun

AU - Greiner, Timothy Charles

AU - Weisenburger, Dennis D.

AU - Rimsza, Lisa

AU - Rosenwald, Andreas

AU - Ott, German

AU - Delabie, Jan

AU - Campo, Elias

AU - Braziel, Rita M.

AU - Gascoyne, Randy D.

AU - Cook, James R.

AU - Tubbs, Raymond R.

AU - Jaffe, Elaine S.

AU - Armitage, James Olen

AU - Vose, Julie Marie

AU - Staudt, Louis M.

AU - McKeithan, Timothy W.

AU - Chan, Wing C.

AU - Ye, B. Hilda

AU - Fu, Kai

PY - 2013/12/30

Y1 - 2013/12/30

N2 - Purpose We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. Patients and Methods By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. Results PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P < .025). Conclusion STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.

AB - Purpose We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. Patients and Methods By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. Results PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P < .025). Conclusion STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.

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