SYK inhibition and response prediction in diffuse large B-cell lymphoma
SYK inhibition and response prediction in diffuse large B-cell lymphoma
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DOI：
10.1182/blood-2011-02-333773
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发表时间：
2011-12-08
期刊：
影响因子：
20.3
通讯作者：
Wang, Y. Lynn
中科院分区：
文献类型：
--
作者：
Cheng, Shuhua;Coffey, Greg;Wang, Y. Lynn
弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤类型，SYK在其发病机制中的作用尚未完全了解。使用组织微阵列，我们首次证明了SYK蛋白在61例原发性人DLBCL组织中的27例（44%）中被激活。在DLBCL细胞系中，7个对高度特异性的SYK抑制剂PRT 060318敏感，3个对高度特异性的SYK抑制剂PRT 060318耐药。在敏感的DLBCL细胞中，SYK抑制阻断了G（1）-S转换并引起细胞周期停滞。通过使用siRNA对SYK进行遗传减少来再现这种效果。对BCR信号通路的详细分析表明，SYK抑制PLC γ 2和AKT的结果，而不是ERK 1/2，是细胞周期停滞的原因。这些关键分子的基因敲低减缓了淋巴瘤细胞的增殖。此外，在原发性淋巴瘤细胞中，BCR信号传导可被PRT 060318阻断。总之，这些发现提供了对淋巴瘤细胞生长所需的细胞途径的见解，并支持将SYK抑制视为DLBCL的潜在有用疗法的理由。结果进一步表明，在特定SYK抑制剂的前瞻性临床试验中，使用PLC γ 2和AKT作为生物标志物来预测治疗反应的可能性。（血。2011;118（24）：6342-6352）
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the role of SYK in its pathogenesis is not completely understood. Using tissue microarray, we demonstrated for the first time that SYK protein is activated in 27 of 61 (44%) primary human DLBCL tissues. Among DLBCL cell lines, 7 were sensitive and 3 were resistant to a highly specific SYK inhibitor, PRT060318. In sensitive DLBCL cells, SYK inhibition blocked the G(1)-S transition and caused cell-cycle arrest. This effect was reproduced by genetic reduction of SYK using siRNA. Adetailed analysis of the BCR signaling pathways revealed that the consequence of SYK inhibition on PLC gamma 2 and AKT, as opposed to ERK1/2, was responsible for cell-cycle arrest. Genetic knock-down of these key molecules decelerated the proliferation of lymphoma cells. In addition, BCR signaling can be blocked by PRT060318 in primary lymphoma cells. Together, these findings provide insights into cellular pathways required for lymphoma cell growth and support the rationale for considering SYK inhibition as a potentially useful therapy for DLBCL. The results further suggest the possibility of using PLC gamma 2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of specific SYK inhibitors. (Blood. 2011;118(24):6342-6352)