Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan.
Mol Cancer Ther. 2010 Dec;9(12):3386-95. doi: 10.1158/1535-7163.MCT-10-0416.
Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease in which the Jak2/Stat5 pathway is constitutively activated. This study found that AZ960, a novel inhibitor of Jak2 kinase, effectively induced growth arrest and apoptosis of human T-cell lymphotropic virus type 1, HTLV-1-infected T cells (MT-1 and MT-2) in parallel with downregulation of the phosphorylated forms of Jak2 and Bcl-2 family proteins including Bcl-2 and Mcl-1. Interestingly, AZ960 increased levels of Bcl-xL in MT-1 and MT-2 cells in association with accumulation of cAMP response element-binding protein bound to the Bcl-xL promoter as measured by chromatin immunoprecipitation assay. Importantly, genetic inhibition of Bcl-xL by a small interfering RNA potentiated antiproliferative effects of AZ960 in MT-1 cells. Taken together, Jak2 is an attractive molecular target for treatment of ATL. Concomitant blockade of Jak2 and Bcl-xL may be a promising treatment strategy for this lethal disease.
成人 T 细胞白血病/淋巴瘤 (ATL) 是一种高度侵袭性疾病，其中 Jak2/Stat5 通路持续激活。本研究发现，新型 Jak2 激酶抑制剂 AZ960 可有效诱导人类 T 细胞嗜淋巴细胞病毒 1（HTLV-1）感染的 T 细胞（MT-1 和 MT-2）的生长停滞和凋亡，同时下调磷酸化形式的 Jak2 和 Bcl-2 家族蛋白，包括 Bcl-2 和 Mcl-1。有趣的是，AZ960 增加了 MT-1 和 MT-2 细胞中 Bcl-xL 的水平，与染色质免疫沉淀分析测定的 Bcl-xL 启动子结合的 cAMP 反应元件结合蛋白的积累有关。重要的是，通过小干扰 RNA 抑制 Bcl-xL 的遗传抑制增强了 AZ960 在 MT-1 细胞中的抗增殖作用。总之，Jak2 是治疗 ATL 的有吸引力的分子靶标。Jak2 和 Bcl-xL 的同时阻断可能是治疗这种致命疾病的有前途的治疗策略。
