Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas.
Diffuse large B-cell lymphoma (DLBCL) consists of at least 2 phenotypic subtypes; that is, the germinal center B-cell-like (GCB-DLBCL) and the activated B-cell-like (ABC-DLBCL) groups. It has been shown that GCB-DLBCL responds favorably to chemotherapy and expresses high levels of BCL6, a transcription repressor known to play a causative role in lymphomagenesis. In comparison, ABC-DLBCL has lower levels of BCL6, constitutively activated nuclear factor-kappaB, and tends to be refractory to chemotherapy. Here, we report that the STAT3 gene is a transcriptional target of BCL6. As a result, high-level STAT3 expression and activation are preferentially detected in ABC-DLBCL and BCL6-negative normal germinal center B cells. Most importantly, inactivating STAT3 by either AG490 or small interference RNA in ABC-DLBCL cells inhibits cell proliferation and triggers apoptosis. These phenotypes are accompanied by decreased expression of several known STAT3 target genes, including c-Myc, JunB, and Mcl-1, and increased expression of the cell- cycle inhibitor p27. In addition to identifying STAT3 as a novel BCL6 target gene, our results define a second oncogenic pathway, STAT3 activation, which operates in ABC-DLBCL, suggesting that STAT3 may be a new therapeutic target in these aggressive lymphomas.
Ding
B Belinda
BB
Departments of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Yu
J Jessica
JJ
Yu
Raymond Y-L
RY
Mendez
Lourdes M
LM
Shaknovich
Rita
R
Zhang
Yonghui
Y
Cattoretti
Giorgio
G
Ye
B Hilda
BH
D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D020032:Tyrphostins / Q000494:pharmacology
C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide