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

B. Belinda Ding, J. Jessica Yu, Raymond Y L Yu, Lourdes M. Mendez, Rita Shaknovich, Yonghui Zhang, Giorgio Cattoretti, B. Hilda Ye

Research output: Contribution to journalArticle

193 Citations (Scopus)

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, ABCDLBCL has lower levels of BCL6, constitutively activated nuclear factor-κB, 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 ABCDLBCL 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 ABCDLBCL, suggesting that STAT3 may be a new therapeutic target in these aggressive lymphomas.

Original languageEnglish (US)
Pages (from-to)1515-1523
Number of pages9
JournalBlood
Volume111
Issue number3
DOIs
StatePublished - 2008

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Lymphoma, Large B-Cell, Diffuse
Cell proliferation
Cell Survival
B-Lymphocytes
Cells
Cell Proliferation
Germinal Center
B-Cell Lymphoma
Chemotherapy
Genes
Drug Therapy
myc Genes
Chemical activation
RNA Interference
Lymphoma
Transcription
Cell Cycle
Refractory materials
Apoptosis
Phenotype

ASJC Scopus subject areas

  • Hematology

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Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. / Ding, B. Belinda; Yu, J. Jessica; Yu, Raymond Y L; Mendez, Lourdes M.; Shaknovich, Rita; Zhang, Yonghui; Cattoretti, Giorgio; Ye, B. Hilda.

In: Blood, Vol. 111, No. 3, 2008, p. 1515-1523.

Research output: Contribution to journalArticle

Ding, B. Belinda ; Yu, J. Jessica ; Yu, Raymond Y L ; Mendez, Lourdes M. ; Shaknovich, Rita ; Zhang, Yonghui ; Cattoretti, Giorgio ; Ye, B. Hilda. / Constitutively activated STAT3 promotes cell proliferation and survival in the activated B-cell subtype of diffuse large B-cell lymphomas. In: Blood. 2008 ; Vol. 111, No. 3. pp. 1515-1523.
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AU - Cattoretti, Giorgio

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AB - 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, ABCDLBCL has lower levels of BCL6, constitutively activated nuclear factor-κB, 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 ABCDLBCL 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 ABCDLBCL, suggesting that STAT3 may be a new therapeutic target in these aggressive lymphomas.

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