Anomalous constitutive Src kinase activity promotes B lymphoma survival and growth.
Anomalous constitutive Src kinase activity promotes B lymphoma survival and growth.
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DOI：
10.1186/1476-4598-8-132
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发表时间：
2009-12-31
期刊：
影响因子：
37.3
通讯作者：
Bondada S
中科院分区：
文献类型：
--
作者：
Ke J;Chelvarajan RL;Sindhava V;Robertson DA;Lekakis L;Jennings CD;Bondada S
以前我们已经证明B细胞受体(BCR)的表达和B细胞受体信号通路对于B淋巴瘤细胞的基础生长是重要的。特别是，我们已经证明，非src家族蛋白酪氨酸激酶Syk的激活以及介导BCR信号的丝裂原激活蛋白激酶(MAPK)、ERK和JNK是B淋巴瘤细胞结构性生长所必需的。由于已知bcr辅受体Ig-α和Ig-β的磷酸化需要像Lyn这样的src家族蛋白酪氨酸激酶(SFK)，我们推测在B淋巴瘤细胞中将有一个或多个SFK被结构性激活，并且可能是B淋巴瘤生长所必需的。在许多小鼠和人类B淋巴瘤细胞系和原发淋巴瘤样本中，SRC激酶活性被发现具有结构性高活性。SFKs、PP1和PP2的特异性药理抑制剂对小鼠和人B淋巴瘤的增殖均有抑制作用，且呈剂量依赖关系。重要的是，口服bcr-abl和sfk双重特异性抑制剂达沙替尼(BMS-354825)在体外抑制纳米分子范围内的B淋巴瘤的生长，并在体内强烈抑制小鼠淋巴瘤的生长。在SFK中，Lyn主要是磷酸化的，Lyn特异性的小干扰RNA抑制B淋巴瘤的生长，支持Lyn在B淋巴瘤生长中的重要作用。抑制SFK活性可阻断BCR介导的信号通路。PMA或CpG可部分逆转SFK抑制所致的生长抑制。尽管阻断SFK活性抑制了一些B淋巴瘤的生长，但一些淋巴瘤，如SUDHL-4、SUDHL-6、OCI-Ly3和OCI-Ly10，由于抗凋亡蛋白Bcl2和Bclxl的表达增加而更具耐药性。这些研究进一步支持了我们的观点，即BCR信号通路对于已建立的B淋巴瘤细胞的持续生长是重要的。BCR途径中的一些中间体是潜在的免疫治疗靶点。特别是，单独抑制SFK活性或与抑制生存期的Bcl-2蛋白协同抑制有望为B淋巴瘤患者开发更有效的治疗方法。
Previously we have shown that B cell receptor (BCR) expression and B cell receptor signaling pathways are important for the basal growth of B lymphoma cells. In particular we have shown that the activation of Syk, a non-src family protein tyrosine kinase and the mitogen activated protein kinases (MAPK), ERK and JNK that mediate BCR signals are required for the constitutive growth of B lymphoma cells. Since src family protein tyrosine kinases (SFKs) like Lyn are known to be needed for the phosphorylation of BCR co-receptors, Ig-α and Ig-β, we hypothesized that one or more SFKs will be constitutively activated in B lymphoma cells and may be necessary for B lymphoma growth. Src kinase activity was found to be constitutively high in many murine and human B lymphoma cell lines and primary lymphoma samples. The specific pharmacological inhibitors of SFKs, PP1 and PP2 inhibited the proliferation of a number of both murine and human B lymphomas in a dose-dependent manner. Importantly, dasatinib (BMS-354825), an oral dual BCR-ABL and SFK specific inhibitor inhibited the growth of B lymphomas in the nanomolar range in vitro and strongly inhibited a mouse lymphoma growth in vivo. Among the SFKs, Lyn is predominantly phosphorylated and Lyn-specific small interfering RNA inhibited the growth of B lymphomas, supporting an important role for Lyn in B lymphoma growth. Suppression of SFK activity blocks BCR mediated signaling pathways. PMA or CpG can partially reverse the growth inhibition induced by SFK inhibition. Although blocking SFK activity inhibited the growth of a number of B lymphomas, some lymphomas such as SudHL-4, SudHL-6, OCI-Ly3 and OCI-Ly10 are more resistant due to an increased expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. These studies further support our concept that BCR signaling pathways are important for the continued growth of established B lymphoma cells. Some of the intermediates in this BCR pathway are potential immunotherapeutic targets. In particular, inhibition of SFK activity alone or in synergy with inhibition of the prosurvival Bcl-2 proteins holds promise in developing more effective treatments for B lymphoma patients.
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影响因子：
20.3
作者：
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通讯作者：
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6.8
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