Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH;
Blood. 2014 Feb 20;123(8):1207-13. doi: 10.1182/blood-2013-07-515361. Epub 2013 Dec 5.
Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive activity in CLL and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we used patient samples and the Eμ-TCL1 (TCL1) transgenic mouse model of CLL, which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by small interfering RNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.
慢性淋巴细胞白血病（CLL）的特征是 B 细胞受体（BCR）信号通路的组成性激活，但 BCR 对抗原连接的反应性不同。布鲁顿酪氨酸激酶（BTK）在 CLL 中表现出组成性活性，是伊布替尼的不可逆抑制剂的靶点，伊布替尼是一种口服生物可利用的激酶抑制剂，在 CLL 中表现出出色的活性。然而，其他可逆和不可逆 BTK 抑制剂在 CLL 中的早期临床结果并不那么有希望，这引发了一个问题，即 BTK 激酶活性是否是伊布替尼的重要靶点，以及在 CLL 中也是如此。为了确定 BTK 在 CLL 中的作用，我们使用了患者样本和 Eμ-TCL1（TCL1）转基因 CLL 小鼠模型，该模型导致自发性白血病的发展。通过小干扰 RNA 抑制原代人 CLL 细胞中的 BTK 可促进细胞凋亡。通过靶向基因失活或伊布替尼在 TCL1 小鼠中抑制 BTK 激酶活性可显著延迟 CLL 的发展，这表明 BTK 是 CLL 发展和扩张的关键激酶，因此是伊布替尼的重要靶点。总的来说，我们的数据证实了激酶功能性 BTK 在 CLL 中的重要性。
