Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia
Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia
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阻断 ATM 依赖性 NF-κB 通路可克服利基保护并改善急性淋巴细胞白血病的化疗反应
DOI：
10.1038/s41375-019-0458-0
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发表时间：
2019-10-01
期刊：
影响因子：
11.4
通讯作者：
Zhou, Bin-Bing S.
中科院分区：
文献类型：
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作者：
Chen, Ya-Li;Tang, Chao;Zhou, Bin-Bing S.
骨髓（BM）生态位对急性淋巴细胞白血病（ALL）细胞分泌的化疗诱导的细胞因子做出反应，并保护残留细胞免受体内化疗的影响。然而，化疗诱导细胞因子的潜在分子机制仍不清楚。在这里，我们发现化疗药物（例如 Ara-C、DNR、6-MP）在体外诱导 ALL 细胞系和原代细胞中生态位保护细胞因子（GDF15、CCL3 和 CCL4）的表达。化疗后ATM和NF-κB通路被激活，这些通路的药理或基因抑制显着逆转了细胞因子的上调。此外，化疗诱导的NF-κB激活依赖于ATM-TRAF6信号传导，NF-κB转录因子p65直接调节细胞因子的表达。此外，我们发现，在 ALL 异种移植小鼠模型中，Ara-C 治疗后，ATM 和 p65 的药理学和遗传扰动均显着减少了残留的 ALL 细胞。总之，这些结果表明 ATM 依赖性 NF-κB 激活介导化疗诱导的细胞因子和 ALL 对化疗药物的耐药性。抑制 ATM 依赖性 NF-κB 通路可以使 ALL 对化疗药物敏感，为根除残留的化疗耐药 ALL 细胞提供新策略。
Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.