Bcl-2 overexpression leads to increases in suppressor of cytokine signaling-3 expression in B cells and de novo follicular lymphoma.
Bcl-2 overexpression leads to increases in suppressor of cytokine signaling-3 expression in B cells and de novo follicular lymphoma.
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DOI：
10.1158/1541-7786.620.2.11
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发表时间：
2004-11
期刊：
影响因子：
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通讯作者：
G. Vanasse;R. Winn;S. Rodov;A. Zieske;John T. Li;J. Tupper;Jingjing Tang;E. Raines;M. Peters;K. Y. Yeung;J. Harlan
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文献类型：
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作者：
G. Vanasse;R. Winn;S. Rodov;A. Zieske;John T. Li;J. Tupper;Jingjing Tang;E. Raines;M. Peters;K. Y. Yeung;J. Harlan
t（14; 18）（q32; q21），导致B细胞白血病/淋巴瘤-2（Bcl-2）表达失调，代表了人类滤泡性淋巴瘤的遗传标志。大量证据支持这样的假设，即t（14;18）和Bcl-2过表达是必要的，但不是肿瘤转化的唯一原因，并且需要协同遗传紊乱才能发生肿瘤转化。为了研究与Bcl-2合作影响肿瘤转化的重要细胞信号传导途径的基因，我们使用寡核苷酸微阵列来确定从Emu-Bcl-2转基因小鼠和野生型同窝对照小鼠分离的CD 19 + B细胞中的差异基因表达模式。在Emu-Bcl-2转基因小鼠中，57个基因被诱导表达，94个基因被抑制≥ 2倍（P < 0.05）。细胞因子信号转导抑制因子3（SOCS 3）基因在Emu-Bcl-2转基因小鼠的B细胞中过表达5倍。Bcl-2在小鼠胚胎成纤维细胞-1和造血细胞系中的过表达导致SOCS 3蛋白的诱导，表明SOCS 3诱导的Bcl-2相关机制。用SOCS 3抗血清对一组原发性滤泡性淋巴瘤患者的组织进行免疫组化，发现在滤泡中心细胞区域内，SOCS 3蛋白显著过表达，仅限于肿瘤性滤泡性淋巴瘤细胞，并在12例原发性滤泡性淋巴瘤病例中的9例中与Bcl-2表达共定位。与此相反，SOCS 3蛋白的表达没有检测到良性增生扁桃体组织的滤泡中心细胞区域。这些数据表明，Bcl-2过表达导致激活的信号转导和转录激活因子3（STAT 3）的诱导和SOCS 3的诱导，这可能有助于滤泡性淋巴瘤的发病机制。
The t(14;18)(q32;q21), resulting in deregulated expression of B-cell-leukemia/lymphoma-2 (Bcl-2), represents the genetic hallmark in human follicular lymphomas. Substantial evidence supports the hypothesis that the t(14;18) and Bcl-2 overexpression are necessary but not solely responsible for neoplastic transformation and require cooperating genetic derangements for neoplastic transformation to occur. To investigate genes that cooperate with Bcl-2 to influence cellular signaling pathways important for neoplastic transformation, we used oligonucleotide microarrays to determine differential gene expression patterns in CD19+ B cells isolated from Emu-Bcl-2 transgenic mice and wild-type littermate control mice. Fifty-seven genes were induced and 94 genes were repressed by > or =2-fold in Emu-Bcl-2 transgenic mice (P < 0.05). The suppressor of cytokine signaling-3 (SOCS3) gene was found to be overexpressed 5-fold in B cells from Emu-Bcl-2 transgenic mice. Overexpression of Bcl-2 in both mouse embryo fibroblast-1 and hematopoietic cell lines resulted in induction of SOCS3 protein, suggesting a Bcl-2-associated mechanism underlying SOCS3 induction. Immunohistochemistry with SOCS3 antisera on tissue from a cohort of patients with de novo follicular lymphoma revealed marked overexpression of SOCS3 protein that, within the follicular center cell region, was limited to neoplastic follicular lymphoma cells and colocalized with Bcl-2 expression in 9 of 12 de novo follicular lymphoma cases examined. In contrast, SOCS3 protein expression was not detected in the follicular center cell region of benign hyperplastic tonsil tissue. These data suggest that Bcl-2 overexpression leads to the induction of activated signal transducer and activator of transcription 3 (STAT3) and to the induction of SOCS3, which may contribute to the pathogenesis of follicular lymphoma.