Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis.
Chronic lymphocytic leukemia B cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis.
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DOI：
10.1172/jci22094
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发表时间：
2005-02
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影响因子：
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通讯作者：
Antonella Contri;A. Brunati;L. Trentin;A. Cabrelle;M. Miorin;L. Cesaro;L. Pinna;R. Zambello;G. Semenzato;A. Donella‐Deana
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作者：
Antonella Contri;A. Brunati;L. Trentin;A. Cabrelle;M. Miorin;L. Cesaro;L. Pinna;R. Zambello;G. Semenzato;A. Donella‐Deana
B细胞慢性淋巴细胞性白血病（B-CLL）是一种肿瘤性疾病，其特征在于由于不受控制的生长和对凋亡的抵抗而导致B淋巴细胞的积聚。对40例慢性淋巴细胞白血病患者新鲜分离的B细胞的分析表明，Src激酶林恩（将B细胞受体与下游信号传导偶联的开关分子）显示出异常特性。与正常B淋巴细胞相比，林恩在白血病细胞中蛋白质水平上显著过表达，在胞质溶胶中存在大量的激酶。而在正常B淋巴细胞中，林恩激活依赖于B细胞受体刺激，在静息恶性细胞中，激酶的组成性活性导致高基础蛋白酪氨酸磷酸化和对IgM连接的低反应性。向白血病细胞培养物中加入林恩抑制剂PP 2和SU 6656可恢复细胞凋亡，用诱导细胞凋亡的药物治疗恶性细胞可降低酪氨酸激酶的活性和数量。这些发现表明高基础林恩活性与白血病细胞诱导凋亡的缺陷之间存在直接相关性。他们还支持林恩在B-CLL发病机制中的关键作用，并确定这种酪氨酸激酶作为潜在的治疗靶点。
B cell chronic lymphocytic leukemia (B-CLL) is a neoplastic disorder characterized by accumulation of B lymphocytes due to uncontrolled growth and resistance to apoptosis. Analysis of B cells freshly isolated from 40 patients with chronic lymphocytic leukemia demonstrated that the Src kinase Lyn, the switch molecule that couples the B cell receptor to downstream signaling, displays anomalous properties. Lyn is remarkably overexpressed at the protein level in leukemic cells as compared with normal B lymphocytes, with a substantial aliquot of the kinase anomalously present in the cytosol. Whereas in normal B lymphocytes Lyn activation is dependent on B cell-receptor stimulation, in resting malignant cells, the constitutive activity of the kinase accounts for high basal protein tyrosine phosphorylation and low responsiveness to IgM ligation. Addition of the Lyn inhibitors PP2 and SU6656 to leukemic cell cultures restores cell apoptosis, and treatment of malignant cells with drugs that induce cell apoptosis decreases both activity and amount of the tyrosine kinase. These findings suggest a direct correlation between high basal Lyn activity and defects in the induction of apoptosis in leukemic cells. They also support a critical role for Lyn in B-CLL pathogenesis and identify this tyrosine kinase as a potential therapeutic target.