Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
Blood. 2011 Dec 8;118(24):6342-52. doi: 10.1182/blood-2011-02-333773. Epub 2011 Oct 24.
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. A detailed analysis of the BCR signaling pathways revealed that the consequence of SYK inhibition on PLCγ2 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 PLCγ2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of specific SYK inhibitors.
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，但其发病机制中 SYK 的作用尚不完全清楚。本研究应用组织微阵列技术首次证明，27/61（44%）例原发性人类 DLBCL 组织中 SYK 蛋白被激活。在 DLBCL 细胞系中，有 7 种对高度特异的 SYK 抑制剂 PRT060318 敏感，3 种耐药。在敏感的 DLBCL 细胞中，SYK 抑制阻断了 G1-S 期转换并导致细胞周期停滞。这种作用可通过 siRNA 介导的 SYK 基因敲低重现。对 BCR 信号通路的详细分析表明，SYK 抑制对 PLCγ2 和 AKT 的作用，而非 ERK1/2，是导致细胞周期停滞的原因。这些关键分子的基因敲低可减缓淋巴瘤细胞的增殖。此外，PRT060318 可阻断原发性淋巴瘤细胞中的 BCR 信号。这些发现深入了解了淋巴瘤细胞生长所需的细胞通路，并支持将 SYK 抑制作为 DLBCL 潜在有效治疗方法的原理。研究结果进一步提示，PLCγ2 和 AKT 可能作为预测特定 SYK 抑制剂治疗反应的生物标志物，用于未来的临床试验。
