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


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).


CONCLUSIONS
STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.
Xin Huang, Bin Meng, Wenfeng Cao, and Kai Fu, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin; Chengfeng Bi, West China Hospital, West China School of Medicine of Sichuan University, Chengdu, China; Xin Huang, Bin Meng, Javeed Iqbal, Anamarija M. Perry, Wenfeng Cao, Lynette M. Smith, Chengfeng Bi, Chunsun Jiang, Timothy C. Greiner, Dennis D. Weisenburger, James O. Armitage, Julie M. Vose, Timothy W. McKeithan, Wing C. Chan, and Kai Fu, University of Nebraska Medical Center, Omaha, NE; B. Belinda Ding and B. Hilda Ye, Albert Einstein College of Medicine, Bronx, NY; Lisa Rimsza, University of Arizona, Tucson, AZ; Andreas Rosenwald, University of Würzburg, Würzburg, Germany; German Ott and Jan Delabie, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway; Elias Campo, Hospital Clinic, University of Barcelona, Barcelona, Spain; Rita M. Braziel, Oregon Health and Science University, Portland, OR; Randy D. Gascoyne, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; James R. Cook and Raymond R. Tubbs, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH; Elaine S. Jaffe and Louis M. Staudt, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
Xin
X
Huang
Bin
B
Meng
Javeed
J
Iqbal
B Belinda
BB
Ding
Anamarija M
AM
Perry
Wenfeng
W
Cao
Lynette M
LM
Smith
Chengfeng
C
Bi
Chunsun
C
Jiang
Timothy C
TC
Greiner
Dennis D
DD
Weisenburger
Lisa
L
Rimsza
Andreas
A
Rosenwald
German
G
Ott
Jan
J
Delabie
Elias
E
Campo
Rita M
RM
Braziel
Randy D
RD
Gascoyne
James R
JR
Cook
Raymond R
RR
Tubbs
Elaine S
ES
Jaffe
James O
JO
Armitage
Julie M
JM
Vose
Louis M
LM
Staudt
Timothy W
TW
McKeithan
Wing C
WC
Chan
B Hilda
BH
Ye
Kai
K
Fu
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D018951:Antigens, CD20 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D000069283:Rituximab; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone