Le Yi, Xu Luhong, Lu Jiayun, Fang Jianpei, Nardi Valentina, Chai Li, Silberstein Leslie E
Department of Pathology, Joint Program in Transfusion Medicine, Children's Hospital Boston, Karp Research Building, Room 10217, One Blackfan Circle, Boston, MA 02115, USA.
Am J Hematol. 2009 May;84(5):273-8. doi: 10.1002/ajh.21381.
Focal adhesion kinase (FAK) is constitutively activated and tyrosine phosphorylated in BCR/ABL-transformed hematopoietic cells, but the role it plays during leukemogenesis remains unclear. Here, we examined the effects of RNA interference-mediated FAK silencing on leukemogenesis induced by a BCR/ABL-transformed cell line. Transduction of BCR/ABL-BaF3 cells with FAK shRNA inhibited FAK expression and reduced STAT5 phosphorylation, but induced caspase-3 activation. In vitro studies showed that treatment with FAK shRNA resulted in impaired cell proliferation and colony formation, while increasing cell apoptosis. Mice that received transplants of BCR/ABL-BaF3 cells with FAK shRNA displayed significantly prolonged survival time and diminished leukemia progression. In addition, FAK silencing enhanced in vitro and in vivo efficacy of ABL tyrosine kinase inhibitor imatinib in BCR/ABL-BaF3 cells. Our results suggest that FAK is critical for leukemogenesis and might be a potential target for leukemia therapy.
粘着斑激酶（FAK）在BCR/ABL转化的造血细胞中持续激活并发生酪氨酸磷酸化，但其在白血病发生过程中所起的作用仍不清楚。在此，我们研究了RNA干扰介导的FAK沉默对BCR/ABL转化细胞系诱导的白血病发生的影响。用FAK短发夹RNA（shRNA）转导BCR/ABL-BaF3细胞可抑制FAK表达并降低STAT5磷酸化，但诱导caspase-3激活。体外研究表明，用FAK shRNA处理导致细胞增殖和集落形成受损，同时增加细胞凋亡。接受用FAK shRNA转导的BCR/ABL-BaF3细胞移植的小鼠存活时间显著延长，白血病进展减缓。此外，FAK沉默增强了ABL酪氨酸激酶抑制剂伊马替尼对BCR/ABL-BaF3细胞的体外和体内疗效。我们的结果表明，FAK对白血病发生至关重要，可能是白血病治疗的一个潜在靶点。
