Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2.
Targeting STAT5 in hematologic malignancies through inhibition of the bromodomain and extra-terminal (BET) bromodomain protein BRD2.
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DOI：
10.1158/1535-7163.mct-13-0341
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发表时间：
2014-05
影响因子：
5.7
通讯作者：
Frank DA
中科院分区：
文献类型：
--
作者：
Liu S;Walker SR;Nelson EA;Cerulli R;Xiang M;Toniolo PA;Qi J;Stone RM;Wadleigh M;Bradner JE;Frank DA
转录因子信号转导子和转录激活子5（STAT5）在广泛的白血病和淋巴瘤中被组成性激活，并驱动增殖、存活和自我更新所必需的基因的表达。因此，靶向STAT5是血液恶性肿瘤的一种有吸引力的治疗策略。鉴于含溴结构域蛋白在转录调节中的重要性，我们考虑了药理学溴结构域抑制剂可以抑制STAT 5依赖性基因表达的假设。我们发现小分子布罗莫结构域和末端外（BET）布罗莫结构域抑制剂JQ1降低异源报告基因和内源性STAT5靶基因两者的STAT5依赖性（但不是STAT3依赖性）转录。JQ1在具有组成性STAT5活化或通过细胞因子刺激诱导活化的白血病和淋巴瘤细胞中降低STAT5功能。在BET布罗莫结构域蛋白质亚家族中，似乎BRD2是STAT5活性的关键介体。在急性T细胞淋巴母细胞白血病的实验模型中，其中活化的STAT5有助于白血病细胞存活，Brd2敲低或JQ1治疗显示出与酪氨酸激酶抑制剂在诱导白血病细胞凋亡中的强协同作用。相比之下，从富含正常造血前体细胞的脐带血中分离的单核细胞不受这些组合的影响。这些发现表明BRD2和STAT5之间存在独特的功能关联，并表明JQ1和酪氨酸激酶抑制剂的组合可能是治疗由组成性STAT5激活驱动的白血病和淋巴瘤的重要合理策略。
The transcription factor signal transducer and activator of transcription 5 (STAT5) is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematological malignancies. Given the importance of bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacological bromodomain inhibitor could inhibit STAT5-dependent gene expression. We found that the small molecule bromodomain and extra-terminal (BET) bromodomain inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET bromodomain sub-family of proteins, it appears that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knock-down or JQ1 treatment shows strong synergy with tyrosine kinase inhibitors in inducing leukemia cells apoptosis. By contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and tyrosine kinase inhibitors may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation.