Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts.
Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts.
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发表时间：
1998-07
期刊：
影响因子：
11.2
通讯作者：
Z. Xia;M. Baer;A. Block;H. Baumann;M. Wetzler
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作者：
Z. Xia;M. Baer;A. Block;H. Baumann;M. Wetzler
造血细胞因子受体信号传导途径涉及信号转导子和转录激活子 (STAT) 蛋白的激活，推测这些蛋白参与细胞分化。异常的 STAT 亚型（β 形式而不是正常的 α 形式）已被描述，并被发现可阻断受体的正常信号传导途径。 Bcr/Abl 蛋白被认为可以直接激活 STAT，而无需暴露于生长因子。我们询问 STAT 是否在白血病发生中发挥作用。我们分析了 36 名新诊断的急性髓系白血病 (AML) 患者预处理母细胞中 STAT 活性的组成型和诱导型模式，并使用体外和凝胶内激酶测定研究了可能参与 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 形式。分别在 28% 和 22% 患者的样本中发现了 STAT3 和 STAT5 的组成型活性。对外源细胞因子的反应分为两组。一组中的 STAT 活性受到外源细胞因子的调节：一些患者的 STAT 活性增加，但另一些患者的 STAT 活性因细胞因子的反应而降低或消失。第二组细胞因子不敏感。此外，我们在两名原始细胞表现出组成型 STAT 活性的患者中发现了组成型 PTK 活性，这表明 PTK 使用细胞因子受体信号通路来激活 AML 原始细胞中的 STAT，而无需暴露于外源细胞因子。我们的数据表明，(a) 异常 STAT 的组成型表达可能参与阻断 AML 原始细胞的分化，(b) 外源细胞因子可能激活 STAT 抑制途径，(c) 在某些 AML 原始细胞中，PTK 可能激活 STAT。
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.