Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-JUN N-terminal kinase inhibition
Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-JUN N-terminal kinase inhibition
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酪氨酸激酶抑制剂达沙替尼与c-JUN N端激酶抑制剂联合治疗BCR-ABL阳性B细胞急性淋巴细胞白血病
DOI：
10.1186/s13045-020-00912-3
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发表时间：
2020-06-18
影响因子：
28.5
通讯作者：
Ren, Ruibao
中科院分区：
文献类型：
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作者：
Xiao, Xinhua;Liu, Ping;Ren, Ruibao
背景费城染色体 (Ph) 导致融合基因产物 BCR-ABL 的产生和表达，它强调了慢性粒细胞白血病 (CML) 以及部分成人和儿童急性 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患者中显示出显着的临床活性，但其治疗Ph+B-ALL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。方法通过蛋白质印迹分析使用或不使用达沙替尼治疗的人和小鼠 BCR-ABL+B-ALL 细胞中 JNK 信号通路的激活情况。 JNK 受到 RNA 干扰或化学抑制剂（例如 JNK-IN-8）的抑制。通过 CellTiter-Glo® 发光细胞活力测定分析 JNK 抑制（联合或不联合 BCR-ABL TKI 达沙替尼）对 BCR-ABL+B-ALL 细胞的影响。使用 BCR-ABL 诱导的 B-ALL 小鼠模型测试了 JNK-IN-8 和达沙替尼单独或联合使用的体内作用。结果我们发现，c-JUN N 末端激酶 (JNK) 信号通路在人和小鼠 BCR-ABL+B-ALL 细胞中异常激活，但 BCR-ABL TKI 不抑制这些细胞中的 JNK 激活。通过 RNAi 介导的下调或 JNK 抑制剂抑制 JNK 可以显着降低 Ph+B-ALL 细胞的活力。 RNAi 介导的下调或 JNK 抑制剂对 JNK 的抑制也显示出与 BCR-ABL TKI 达沙替尼在体外杀死 Ph+B-ALL 细胞方面的协同作用。此外，与单独使用达沙替尼治疗相比，有效的 JNK 抑制剂 JNK-IN-8 与达沙替尼联合显着改善了 BCR-ABL 诱导的 B-ALL 小鼠的生存率。结论我们的研究结果表明，同时靶向 BCR-ABL 和 JNK 激酶可能是 Ph+B-ALL 的一种有前途的治疗策略。
BackgroundThe 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.MethodsActivation 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.ResultsWe 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.ConclusionsOur findings indicate that simultaneously targeting both BCR-ABL and JNK kinase might serve as a promising therapeutic strategy for Ph+B-ALL.