Battle Traci E, Frank David A
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA.
Blood. 2003 Oct 15;102(8):3016-24. doi: 10.1182/blood-2002-09-2972. Epub 2003 Jul 10.
Bryostatin 1 is known to exhibit in vitro and in vivo activity against chronic lymphocytic leukemia (CLL) cells by inducing their further maturation into plasma-like cells. Signal transducer and activator of transcription (STAT) proteins play a central role in B-lymphocyte growth and function and are aberrantly phosphorylated on serine residues in CLL cells. To determine whether STAT transcription factors are important in Bryostatin 1-induced differentiation of CLL cells, primary CLL cells were examined for signaling events following exposure to Bryostatin 1 in vitro. Western analysis and electrophoretic mobility shift assays revealed that Bryostatin 1 induced tyrosine phosphorylation and DNA binding of STAT1, yet there was no effect on constitutive serine phosphorylation of STAT1. Bryostatin 1-induced STAT1 activation occurred in a manner that was dependent on protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and Janus tyrosine kinase (JAK) activation. Evidence indicates that Bryostatin 1 induces STAT1 activation through an interferon gamma (IFN gamma) autocrine loop. However, STAT1 activation by IFN gamma stimulation alone was not sufficient to induce differentiation. This insufficiency is due to the broader effect on gene expression caused by Bryostatin 1 compared with IFN gamma, as demonstrated by microarray analysis. Both up-regulation of CD22 expression and immunoglobulin M (IgM) production, markers of CLL differentiation, were inhibited by a decoy oligonucleotide for STAT1, indicating that STAT1 is necessary for Bryostatin 1-induced differentiation of CLL cells. This study implicates STAT transcription factors as important mediators of Bryostatin 1-induced differentiation of CLL cells and could possibly lead to improved therapeutic approaches for the treatment of CLL.
已知苔藓抑素1通过诱导慢性淋巴细胞白血病（CLL）细胞进一步成熟为浆样细胞，在体外和体内对其表现出活性。信号转导和转录激活因子（STAT）蛋白在B淋巴细胞的生长和功能中起核心作用，并且在CLL细胞中的丝氨酸残基上异常磷酸化。为了确定STAT转录因子在苔藓抑素1诱导的CLL细胞分化中是否重要，对原代CLL细胞在体外暴露于苔藓抑素1后的信号转导事件进行了检测。蛋白质印迹分析和电泳迁移率变动分析显示，苔藓抑素1诱导了STAT1的酪氨酸磷酸化和DNA结合，但对STAT1的组成型丝氨酸磷酸化没有影响。苔藓抑素1诱导的STAT1激活以依赖蛋白激酶C（PKC）、丝裂原活化蛋白激酶（MAPK）和Janus酪氨酸激酶（JAK）激活的方式发生。有证据表明，苔藓抑素1通过干扰素γ（IFNγ）自分泌环诱导STAT1激活。然而，单独的IFNγ刺激激活STAT1不足以诱导分化。如微阵列分析所示，这种不足是由于与IFNγ相比，苔藓抑素1对基因表达有更广泛的影响。STAT1的诱饵寡核苷酸抑制了CD22表达上调和免疫球蛋白M（IgM）产生，这两者都是CLL分化的标志物，表明STAT1是苔藓抑素1诱导CLL细胞分化所必需的。这项研究表明STAT转录因子是苔藓抑素1诱导CLL细胞分化的重要介质，并可能导致改善CLL治疗的方法。
