酪氨酸激酶抑制剂达沙替尼联合 c-JUN N-末端激酶抑制治疗 BCR-ABL 阳性 B 细胞急性淋巴细胞白血病。
Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-JUN N-terminal kinase inhibition.
机构信息
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
出版信息
J Hematol Oncol. 2020 Jun 18;13(1):80. doi: 10.1186/s13045-020-00912-3.
BACKGROUND
The Philadelphia chromosome (Ph), which leads to the creation and expression of the fusion gene product BCR-ABL, underlines the pathogenesis of chronic myelogenous leukemia (CML) and a fraction of adult and pediatric acute B-lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitors (TKIs) have shown a remarkable clinical activity in patients with CML, but their efficacy in treating Ph B-ALL is limited. Identifying additional therapeutic targets is important for the effective treatment of Ph B-ALL.
METHODS
Activation of the JNK signaling pathway in human and mouse BCR-ABL B-ALL cells with or without dasatinib treatment was analyzed by Western blotting. JNK was inhibited either by RNA interference or chemical inhibitors, such as JNK-IN-8. The effect of JNK inhibition with or without BCR-ABL TKI dasatinib on BCR-ABL B-ALL cells was analyzed by the CellTiter-Glo® Luminescent Cell Viability Assay. The in vivo effects of JNK-IN-8 and dasatinib alone or in combination were tested using a BCR-ABL induced B-ALL mouse model.
RESULTS
We found that the c-JUN N-terminal kinase (JNK) signaling pathway is abnormally activated in both human and mouse BCR-ABL B-ALL cells, but the BCR-ABL TKI does not inhibit JNK activation in these cells. Inhibition of JNK, either by RNAi-mediated downregulation or by JNK inhibitors, could significantly reduce viability of Ph B-ALL cells. JNK inhibition by RNAi-mediated downregulation or JNK inhibitors also showed a synergistic effect with the BCR-ABL TKI, dasatinib, in killing Ph B-ALL cells in vitro. Furthermore, a potent JNK inhibitor, JNK-IN-8, in combination with dasatinib markedly improved the survival of mice with BCR-ABL induced B-ALL, as compared to the treatment with dasatinib alone.
CONCLUSIONS
Our findings indicate that simultaneously targeting both BCR-ABL and JNK kinase might serve as a promising therapeutic strategy for Ph B-ALL.
背景
费城染色体（Ph）导致融合基因产物 BCR-ABL 的产生和表达，这是慢性髓细胞白血病（CML）和部分成人及儿童急性 B 淋巴细胞白血病（B-ALL）的发病机制。BCR-ABL 酪氨酸激酶抑制剂（TKI）在 CML 患者中表现出显著的临床活性，但它们在治疗 Ph B-ALL 方面的疗效有限。确定其他治疗靶点对于有效治疗 Ph B-ALL 非常重要。
方法
通过 Western blot 分析有或无达沙替尼治疗的人源和鼠源 BCR-ABL B-ALL 细胞中 JNK 信号通路的激活情况。通过 RNA 干扰或化学抑制剂（如 JNK-IN-8）抑制 JNK。通过 CellTiter-Glo®发光细胞活力测定法分析 JNK 抑制与 BCR-ABL TKI 达沙替尼对 BCR-ABL B-ALL 细胞的影响。单独使用 JNK-IN-8 和达沙替尼或联合使用 JNK-IN-8 和达沙替尼在 BCR-ABL 诱导的 B-ALL 小鼠模型中测试其体内效果。
结果
我们发现 c-JUN N-末端激酶（JNK）信号通路在人源和鼠源 BCR-ABL B-ALL 细胞中均异常激活，但 BCR-ABL TKI 并不能抑制这些细胞中的 JNK 激活。通过 RNAi 介导的下调或 JNK 抑制剂抑制 JNK 可显著降低 Ph B-ALL 细胞的活力。通过 RNAi 介导的下调或 JNK 抑制剂抑制 JNK 也与 BCR-ABL TKI 达沙替尼在体外杀死 Ph B-ALL 细胞表现出协同作用。此外，一种有效的 JNK 抑制剂 JNK-IN-8 与达沙替尼联合使用可显著改善 BCR-ABL 诱导的 B-ALL 小鼠的存活，与单独使用达沙替尼相比。
结论
我们的研究结果表明，同时靶向 BCR-ABL 和 JNK 激酶可能成为治疗 Ph B-ALL 的一种有前途的治疗策略。
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