Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
Cancer Cell. 2013 Jun 10;23(6):826-38. doi: 10.1016/j.ccr.2013.05.002.
B cell receptor (BCR) signaling pathway components represent promising treatment targets in diffuse large B cell lymphoma (DLBCL) and additional B cell tumors. BCR signaling activates spleen tyrosine kinase (SYK) and downstream pathways including PI3K/AKT and NF-κB. In previous studies, chemical SYK blockade selectively decreased BCR signaling and induced apoptosis of BCR-dependent DLBCLs. Herein, we characterize distinct SYK/PI3K-dependent survival pathways in DLBCLs with high or low baseline NF-κB activity including selective repression of the pro-apoptotic HRK protein in NF-κB-low tumors. We also define SYK/PI3K-dependent cholesterol biosynthesis as a feed-forward mechanism of maintaining the integrity of BCRs in lipid rafts in DLBCLs with low or high NF-κB. In addition, SYK amplification and PTEN deletion are identified as selective genetic alterations in primary "BCR"-type DLBCLs.
B 细胞受体 (BCR) 信号通路成分是弥漫性大 B 细胞淋巴瘤 (DLBCL) 和其他 B 细胞肿瘤有前途的治疗靶点。BCR 信号激活脾酪氨酸激酶 (SYK) 和下游途径，包括 PI3K/AKT 和 NF-κB。在以前的研究中，化学 SYK 阻断选择性地降低了 BCR 信号，并诱导了 BCR 依赖性 DLBCL 的细胞凋亡。在此，我们描述了 NF-κB 活性高或低的 DLBCL 中不同的 SYK/PI3K 依赖性存活途径，包括 NF-κB 低肿瘤中选择性抑制促凋亡 HRK 蛋白。我们还定义了 SYK/PI3K 依赖性胆固醇生物合成作为在 NF-κB 低或高的 DLBCL 中脂质筏中 BCR 完整性的维持的正反馈机制。此外，SYK 扩增和 PTEN 缺失被鉴定为原发性“BCR”型 DLBCL 中的选择性遗传改变。
