| Description |
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, 6MP, MTX) induce the expression of niche-protecting cytokines (CCL3, CCL4 and GDF15) in both ALL cell lines and primary ALL cells in vitro. The ATM and NF-κB pathways were activated after Ara-C 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 cytokine expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significant decrease the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediates the cytokines induction by chemotherapy and drug resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway sensitizes the ALL to chemotherapeutics, providing a new strategy to eradicate chemo-resistant ALL cells. |
