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., Yu, J., Yu, R., Mendez, L., Shaknovich, R., Zhang, Y., et al. (2008). Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. BLOOD, 111(3), 1515-1523 [10.1182/blood-2007-04-087734].

Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas

CATTORETTI, GIORGIO;
2008

Abstract

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.
Articolo in rivista - Articolo scientifico
Base Sequence ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival ; DNABinding Proteins/genetics/metabolism ; Gene Expression Regulation ; Germinal Center/immunology ; Humans ; Lymphocyte Activation/*immunology ; Lymphoma, Large BCell, Diffuse/classification/*immunology/*metabolism/pathology ; Mutation/genetics ; RNA Interference ; RNA, Messenger/genetics ; STAT3 Transcription Factor/genetics/*metabolism ; Transcription, Genetic/genetics ; Tyrphostins/pharmacology
English
1515
1523
Ding, B., Yu, J., Yu, R., Mendez, L., Shaknovich, R., Zhang, Y., et al. (2008). Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. BLOOD, 111(3), 1515-1523 [10.1182/blood-2007-04-087734].
Ding, B; Yu, J; Yu, R; Mendez, L; Shaknovich, R; Zhang, Y; Cattoretti, G; Ye, B
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/6516
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