Gobessi S, Laurenti L, Longo P G, Carsetti L, Berno V, Sica S, Leone G, Efremov D G
ICGEB Molecular Hematology Group, Campus A Buzzati-Traverso, Rome, Italy.
Leukemia. 2009 Apr;23(4):686-97. doi: 10.1038/leu.2008.346. Epub 2008 Dec 18.
The protein kinase Syk is a key mediator of proximal B-cell receptor (BCR) signaling. Following antigen stimulation, Syk is recruited to the BCR and becomes activated by phosphorylation at Y352. Recently, Syk was found to be constitutively phosphorylated in several common B-cell lymphoma subtypes, indicating a role for antigen-independent Syk activation in the pathogenesis of these diseases. We now report that Syk is constitutively phosphorylated on the activating Y352 residue in chronic lymphocytic leukemia (CLL) B cells. To examine the effects of constitutive Syk activity on intracellular signaling and leukemic cell survival, we performed in vitro studies with the Syk inhibitor R406. Treatment with R406 induced leukemic cell apoptosis in the majority of investigated cases and affected the basal activity or expression of several pro-survival molecules regulated by Syk, including the Akt and extracellular signal-regulated (ERK) kinases, and the anti-apoptotic protein Mcl-1. In addition, R406 prevented the increase in leukemic cell viability induced by sustained BCR engagement and inhibited BCR-induced Akt activation and Mcl-1 upregulation. Collectively, these data identify Syk as a potential target for CLL treatment and suggest that inhibition of this kinase could provide a double therapeutic benefit by disrupting both antigen-dependent and antigen-independent signaling pathways that regulate leukemic cell survival.
蛋白激酶Syk是B细胞受体（BCR）近端信号传导的关键介质。在抗原刺激后，Syk被招募到BCR，并通过Y352位点的磷酸化而被激活。最近，发现Syk在几种常见的B细胞淋巴瘤亚型中组成性磷酸化，这表明在这些疾病的发病机制中存在抗原非依赖性Syk激活作用。我们现在报告，在慢性淋巴细胞白血病（CLL）B细胞中，Syk在激活的Y352残基上组成性磷酸化。为了研究组成性Syk活性对细胞内信号传导和白血病细胞存活的影响，我们使用Syk抑制剂R406进行了体外研究。在大多数研究病例中，用R406处理诱导白血病细胞凋亡，并影响由Syk调节的几种促生存分子的基础活性或表达，包括Akt和细胞外信号调节激酶（ERK），以及抗凋亡蛋白Mcl-1。此外，R406可防止持续BCR结合诱导的白血病细胞活力增加，并抑制BCR诱导的Akt激活和Mcl-1上调。总体而言，这些数据确定Syk是CLL治疗的潜在靶点，并表明抑制该激酶可能通过破坏调节白血病细胞存活的抗原依赖性和抗原非依赖性信号通路而提供双重治疗益处。
