Xia Z, Baer M R, Block A W, Baumann H, Wetzler M
Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Cancer Res. 1998 Jul 15;58(14):3173-80.
Hematopoietic cytokine receptor signaling pathways involve activation of signal transducers and activators of transcription (STAT) proteins, which are postulated to be involved in cellular differentiation. Aberrant STAT isoforms (beta forms rather than the normal alpha forms) have been described and have been found to block the normal signaling pathway from the receptor. Bcr/Abl proteins have been suggested to directly activate STATs, without exposure to growth factors. We asked whether STATs play a role in leukemogenesis. We analyzed constitutive and induced patterns of STAT activity in pretreatment blasts from 36 newly diagnosed acute myeloid leukemia (AML) patients and studied protein tyrosine kinases (PTKs) that may be involved in STAT activity, using in vitro and in-gel kinase assays. The beta forms were expressed in 21 of 27 samples (78%). Constitutive STAT3 and STAT5 activity was found in samples from 28 and 22% of patients, respectively. Response to exogenous cytokines identified two groups. STAT activity in one group was modulated by exogenous cytokines: constitutive STAT activity increased in some patients but decreased or disappeared in response to cytokines in others. The second group was cytokine insensitive. Additionally, we found constitutive PTK activity in two patients whose blasts demonstrated constitutive STAT activity, suggesting that PTKs use cytokine receptor signal pathways to activate STATs in AML blasts without exposure to exogenous cytokines. Our data suggest that (a) constitutive expression of aberrant STATs may be involved in blocking differentiation of AML blasts, (b) exogenous cytokines may activate STAT-inhibitory pathways, and (c) STATs may be activated by PTKs in some AML blasts.
造血细胞因子受体信号通路涉及信号转导及转录激活蛋白（STAT）的激活，据推测其参与细胞分化过程。已有异常的STAT异构体（β型而非正常的α型）被描述，且发现其可阻断受体的正常信号通路。有人提出Bcr/Abl蛋白可直接激活STAT，而无需暴露于生长因子。我们探究了STAT在白血病发生过程中是否发挥作用。我们分析了36例新诊断急性髓系白血病（AML）患者预处理原始细胞中STAT活性的组成性和诱导性模式，并使用体外和凝胶内激酶分析研究了可能参与STAT活性的蛋白酪氨酸激酶（PTK）。27个样本中有21个（78%）表达了β型。分别在28%和22%患者的样本中发现了组成性的STAT3和STAT5活性。对外源性细胞因子的反应确定了两组。一组中的STAT活性受外源性细胞因子调节：一些患者的组成性STAT活性增加，而另一些患者的则在细胞因子作用下降低或消失。第二组对细胞因子不敏感。此外，我们在两名原始细胞表现出组成性STAT活性的患者中发现了组成性PTK活性，这表明PTK在AML原始细胞中利用细胞因子受体信号通路激活STAT，而无需暴露于外源性细胞因子。我们的数据表明：（a）异常STAT的组成性表达可能参与阻断AML原始细胞的分化；（b）外源性细胞因子可能激活STAT抑制通路；（c）在一些AML原始细胞中，STAT可能被PTK激活。
