Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia
Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2010-04-277947
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发表时间：
2010-10-14
期刊：
影响因子：
20.3
通讯作者：
Barata, Joao T.
中科院分区：
文献类型：
--
作者：
Martins, Leila R.;Lucio, Paulo;Barata, Joao T.
蛋白激酶CK 2的表达经常在癌症中失调，越来越多的证据表明CK 2与肿瘤发生有关。在这里，我们表明，CK 2是过度表达和过度激活的慢性淋巴细胞白血病（CLL）。CK 2的抑制诱导CLL细胞的凋亡，而不显著影响正常B和T淋巴细胞。重要的是，这种作用不能通过与OP 9基质细胞共培养来逆转，否则OP 9基质细胞能够从体外自发凋亡中拯救CLL细胞。CK 2抑制后的CLL细胞死亡由PKC（PI 3 K下游靶标）的失活介导，并且与增加的PTEN活性相关，表明CK 2至少部分地通过PI 3 K依赖性信号传导促进CLL细胞存活。尽管CK 2拮抗剂在分析的所有患者样品中诱导CLL细胞的显著凋亡，但对CK 2阻断的敏感性与外周血中CLL细胞的百分比、β 2微球蛋白血清水平和临床分期正相关。这些数据表明，具有侵袭性和晚期疾病的患者亚群可能特别受益于靶向CK 2功能的治疗策略。总的来说，我们的研究表明，CK 2在CLL细胞存活中起着关键作用，为将CK 2抑制剂纳入未来的治疗策略奠定了基础。（血。2010;116（15）：2724-2731）
Expression of protein kinase CK2 is frequently deregulated in cancer and mounting evidence implicates CK2 in tumorigenesis. Here, we show that CK2 is overexpressed and hyperactivated in chronic lymphocytic leukemia (CLL). Inhibition of CK2 induces apoptosis of CLL cells without significantly affecting normal B and T lymphocytes. Importantly, this effect is not reversed by coculture with OP9 stromal cells, which are otherwise capable of rescuing CLL cells from in vitro spontaneous apoptosis. CLL cell death upon CK2 inhibition is mediated by inactivation of PKC, a PI3K downstream target, and correlates with increased PTEN activity, indicating that CK2 promotes CLL cell survival at least in part via PI3K-dependent signaling. Although CK2 antagonists induce significant apoptosis of CLL cells in all patient samples analyzed, sensitivity to CK2 blockade positively correlates with the percentage of CLL cells in the peripheral blood, beta 2 microglobulin serum levels and clinical stage. These data suggest that subsets of patients with aggressive and advanced stage disease may especially benefit from therapeutic strategies targeting CK2 function. Overall, our study indicates that CK2 plays a critical role in CLL cell survival, laying the groundwork for the inclusion of CK2 inhibitors into future therapeutic strategies. ( Blood. 2010;116(15):2724-2731)