伊布替尼
布鲁顿酪氨酸激酶
慢性淋巴细胞白血病
套细胞淋巴瘤
癌症研究
酪氨酸激酶
淋巴瘤
白血病
生物
突变
突变体
断点群集区域
免疫学
信号转导
生物化学
作者
Shuhua Cheng,Guo A,Ping Lü,Jiao Ma,Morton Coleman,Y. Lynn Wang
出处
期刊:Leukemia
[Springer Nature]
日期:2014-09-05
卷期号:29 (4): 895-900
被引量:133
摘要
The Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has produced remarkable clinical response in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. We previously reported the identification of BTK(C481S) mutation in a CLL patient who progressed following 21-month ibrutinib therapy. Initial characterization at structural and biochemical levels revealed that the mutation disrupts the covalent binding of ibrutinib to BTK, reduces its binding affinity and diminishes its ability to inhibit the BTK enzymatic activity. Herein, we further characterized the functional consequences of BTK(C481S) in terms of molecular signaling, gene expression and cellular behavior in the patient, as well as in lymphoma cells transfected with either the wild-type or the mutant BTK constructs. Further, using an in vitro CLL proliferation model, alternative kinase inhibitors that have the potential to overcome ibrutinib resistance were explored.
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