Chai S K, Nichols G L, Rothman P
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York 10032, USA.
J Immunol. 1997 Nov 15;159(10):4720-8.
An important step in the oncogenic transformation of hemopoietic cells and the subsequent development of leukemia is the proliferation of tumor cells in the absence of exogenous growth factors. In most cases of chronic myelocytic leukemia and in some cases of acute myelocytic leukemia and acute lymphocytic leukemia, the bcr-abl oncogene is involved in this process. Although the BCR-Abl oncoprotein demonstrates enhanced tyrosine kinase activity in leukemic cells, the mechanism by which this leads to growth factor independence remains poorly defined. One proposed mechanism is the activation of cytokine signal transduction pathways, possibly by an autocrine loop involving IL-3 and/or granulocyte-macrophage CSF. Examination of several different cell lines expressing BCR-Abl demonstrates that some of these cells have constitutive activation of the JAK/STAT signaling pathway. We have found the constitutive activation of STAT5 in most, but not all, cell lines expressing BCR-Abl. This constitutive activation of STAT5 is variably associated with a corresponding activation of JAK kinases. Ab blocking studies show that the activation of STAT5 in these cell lines cannot be attributed to the activation of an IL-3/granulocyte-macrophage CSF-driven autocrine loop. Interestingly, samples of peripheral blood cells derived from patients with acute myelocytic leukemia and chronic myelocytic leukemia, which express BCR-Abl, demonstrate constitutive activation of STAT family members. These studies suggest that in a variety of leukemic states, BCR-Abl may use a bypass mechanism to activate cytokine signal transduction pathways.
造血细胞致癌转化及随后白血病发展过程中的一个重要步骤是肿瘤细胞在无外源性生长因子情况下的增殖。在大多数慢性粒细胞白血病病例以及一些急性粒细胞白血病和急性淋巴细胞白血病病例中，bcr-abl癌基因参与了这一过程。尽管BCR-Abl癌蛋白在白血病细胞中显示出增强的酪氨酸激酶活性，但导致其不依赖生长因子的机制仍不清楚。一种提出的机制是细胞因子信号转导途径的激活，可能是通过涉及IL-3和/或粒细胞-巨噬细胞集落刺激因子的自分泌环。对几种表达BCR-Abl的不同细胞系的研究表明，其中一些细胞具有JAK/STAT信号通路的组成性激活。我们发现在大多数（但不是全部）表达BCR-Abl的细胞系中STAT5有组成性激活。STAT5的这种组成性激活与JAK激酶的相应激活存在不同程度的关联。抗体阻断研究表明，这些细胞系中STAT5的激活不能归因于IL-3/粒细胞-巨噬细胞集落刺激因子驱动的自分泌环的激活。有趣的是，来自表达BCR-Abl 的急性粒细胞白血病和慢性粒细胞白血病患者的外周血细胞样本显示出STAT家族成员的组成性激活。这些研究表明，在多种白血病状态下，BCR-Abl可能利用一种旁路机制来激活细胞因子信号转导途径。
