Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia
| العنوان: | Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia |
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| المؤلفون: | Zhong-Qun Zhu, Yan Xu, Yan Miao, Wei-Wei Zheng, He Wang, Chao Tang, Li-Li Mu, Bin-Bing S. Zhou, Ming-Hao Li, Hong-Zhuan Chen, Hui-Wen Chen, Shuhong Shen, Hui Li, Zhong-Hua Tang, Lixia Ding, Wen-Li Huang, Jing Chen, Meng-Yi Zhang, Dengli Hong, Hui-Yin Sun, Sheng-Li Liu, Ya-Li Chen, Benshang Li, Fan Yang, Li-Li Song, Cai-Wen Duan |
| المصدر: | Leukemia. 33:2365-2378 |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, medicine.medical_treatment, CCL3, Antineoplastic Agents, Ataxia Telangiectasia Mutated Proteins, Mice, SCID, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Downregulation and upregulation, Mice, Inbred NOD, Cell Line, Tumor, medicine, Animals, Humans, Child, TNF Receptor-Associated Factor 6, Regulation of gene expression, Chemotherapy, Gene Expression Regulation, Leukemic, NF-kappa B, NF-κB, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 030104 developmental biology, medicine.anatomical_structure, Cytokine, Oncology, chemistry, Drug Resistance, Neoplasm, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Cytokines, Female, Bone marrow, Signal Transduction |
| الوصف: | 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. |
| تدمد: | 1476-5551 0887-6924 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::58acb1d802fccaeb37c5ec5e0bc1fcc5 https://doi.org/10.1038/s41375-019-0458-0 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....58acb1d802fccaeb37c5ec5e0bc1fcc5 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14765551 08876924 |
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