Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression
Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression
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DOI：
10.1172/jci9940
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发表时间：
2001-02-01
影响因子：
15.9
通讯作者：
Loughran, TP
中科院分区：
文献类型：
--
作者：
Epling-Burnette, PK;Liu, JH;Loughran, TP
大颗粒淋巴细胞（LGL）白血病的特征是抗原激活的细胞毒性T淋巴细胞的扩增。这些白血病细胞尽管表达高水平的Fas，但对Fas介导的凋亡具有抗性。我们发现，19例白血病LGL显示高水平的活化STAT 3。用JAK选择性酪氨酸激酶抑制剂AG-490治疗白血病LGL诱导细胞凋亡，STAT-DNA结合活性相应降低。此外，使用反义寡核苷酸方法来减少STAT 3表达，我们发现白血病LGL中Fas敏感性恢复，AG-490诱导的白血病LGL凋亡不依赖于Bcl-x（L）或Bcl-2表达。然而，我们发现Bcl-2家族蛋白Mcl-1被AG-490处理显著降低。活化的STAT 3显示结合鼠mcl-1启动子中的SIE相关元件。使用荧光素酶报告基因检测，我们证明了在NIH 3 T3中v-src过表达诱导了mcl-1启动子的STAT 3依赖性转录活性，并增加了内源性Mcl-1蛋白水平。我们得出结论，STAT 3激活导致白血病LGL克隆的积累。这些研究结果表明，调查应集中在新的策略，在治疗LGL白血病的STAT 3靶向。
Large granular lymphocyte (LGL) leukemia is characterized by the expansion of antigen-activated cytocoxic T lymphocytes. These leukemic cells are resistant to Fas-mediated apoptosis despite expressing high levels of Fas. We found that leukemic LGL from 19 patients displayed high levels of activated STAT3. Treatment of leukemic LGL with the JAK-selective tyrosine kinase inhibitor AG-490 induced apoptosis with a corresponding decrease in STAT-DNA binding activity. Moreover, using an antisense oligonucleotide approach to diminish STAT3 expression, we found that Fas sensitivity was restored in leukemic LGL, AG-490-induced apoptosis in leukemic LGL was independent of Bcl-x(L) or Bcl-2 expression. However, we found that the Bcl-2-family protein Mcl-1 was significantly reduced by AG-490 treatment. Activated STAT3 was shown to bind an SIE-related element in the murine, mcl-1 promoter. Using a luciferase reporter assay, we demonstrated that v-src overexpression in NIH3T3 induced STAT3-dependent transcriptional activity from the mcl-1 promoter and increased endogenous Mcl-1 protein levels. We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones. These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia.