On CK2 regulation of chronic lymphocytic leukemia cell viability
On CK2 regulation of chronic lymphocytic leukemia cell viability
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DOI：
10.1007/s11010-011-0947-6
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发表时间：
2011-10-01
影响因子：
4.3
通讯作者：
Barata, Joao T.
中科院分区：
文献类型：
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作者：
Martins, Leila R.;Lucio, Paulo;Barata, Joao T.
对b细胞慢性淋巴细胞白血病（CLL）细胞生存所必需的信号元件的特异性抑制为设计更有效的治疗方法提供了巨大的希望。蛋白丝氨酸/苏氨酸激酶CK2在癌症中经常上调，并且在未经治疗的患者的原发性CLL细胞中过度表达和过度激活。我们已经证明，抑制CK2可诱导CLL细胞凋亡，而对正常淋巴细胞没有显著影响，这表明CK2抑制剂对白血病细胞具有选择性。值得注意的是，虽然与OP9基质细胞共培养和BCR刺激都能促进白血病细胞的体外存活，但它们并不能阻止CK2抑制剂处理的CLL细胞的凋亡。PI3K信号通路先前被证明对CLL细胞活力至关重要，我们在分析的所有患者样本中证实了这一观察结果。此外，我们观察到CK2阻断降低了PTEN磷酸化，导致PTEN活化，CK2抑制后CLL细胞的凋亡是由PKC失活介导的。这表明PI3K/PKC信号通路的激活参与了CK2在CLL细胞中的促生存作用。对CK2抑制的敏感性与ZAP-70或CD38的表达无关，也与IGVH突变状态无关。然而，它与外周血CLL细胞百分比、β 2微球蛋白水平和Binet临床分期呈正相关。CK2似乎在CLL的生物学中起着重要作用，并构成了白血病特异性治疗发展的一个有希望的靶点。
Specific inhibition of signaling elements essential for the viability of B-cell chronic lymphocytic leukemia (CLL) cells offers great promise for the design of more efficient therapies. The protein serine/threonine kinase CK2 is frequently upregulated in cancer, and it is overexpressed and hyperactivated in primary CLL cells from untreated patients. We have shown that inhibition of CK2 induces apoptosis of CLL cells, whereas it does not significantly impact normal lymphocytes, demonstrating the selectivity of the CK2 inhibitors toward leukemia cells. Notably, although co-culture with OP9 stromal cells and BCR stimulation both promote leukemia cell survival in vitro, they do not prevent apoptosis of CLL cells treated with CK2 inhibitors. PI3K signaling pathway was previously shown to be essential for CLL cell viability, an observation we confirmed in all patient samples analyzed. Further, we observed that CK2 blockade decreases PTEN phosphorylation, leading to PTEN activation, and that apoptosis of CLL cells upon CK2 inhibition is mediated by PKC inactivation. This suggests that activation of PI3K/PKC signaling pathway is involved in the pro-survival effects of CK2 in CLL cells. Sensitivity to CK2 inhibition does not correlate with expression of ZAP-70 or CD38, or with IGVH mutation status. However, it positively correlates with the percentage of CLL cells in the peripheral blood, beta 2 microglobulin levels, and Binet clinical stage. CK2 appears to play an important role in the biology of CLL and constitutes a promising target for the development of leukemia-specific therapies.