Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765
Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765
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DOI：
10.1182/blood-2011-01-328484
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发表时间：
2011-06-09
期刊：
影响因子：
20.3
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Herman, Sarah E. M.;Gordon, Amber L.;Byrd, John C.
b细胞受体（BCR）信号在慢性淋巴细胞白血病（CLL）中异常激活。布鲁顿酪氨酸激酶（BTK）对BCR信号传导至关重要，在敲除小鼠模型中，其突变具有相对的B细胞特异性表型。本研究表明，与正常B细胞相比，BTK蛋白和mRNA在CLL中显著过表达。尽管BTK在CLL细胞中并不总是具有组成性活性，但BCR或CD40信号传导伴随着该途径的有效激活。使用不可逆的BTK抑制剂PCI-32765，我们发现CLL细胞的适度凋亡大于正常B细胞。未观察到PCI-32765对t细胞存活的影响。用PCI-32765处理CD40或BCR活化的CLL细胞，可抑制BTK酪氨酸磷酸化，并有效消除由该激酶激活的下游生存途径，包括ERK1/2、PI3K和NF-kappa b。此外，PCI-32765在体外抑制活化诱导的CLL细胞增殖，并有效阻断微环境向CLL细胞提供的生存信号，包括可溶性因子（CD40L、BAFF、IL-6、IL-4和tnf - α）。纤维连接蛋白接触，基质细胞接触。基于这些集体数据，未来在CLL患者的临床试验中，针对BTK使用不可逆抑制剂PCI-32765是有必要的。[血液，2011;117(23):6287-6296]
B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-kappa B. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-alpha), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted. (Blood. 2011; 117(23): 6287-6296)