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Abstract Background Nowadays, acute leukemia (AL) among children has favorable outcome, yet some of them get refractory or relapse mainly due to drug resistance. High-mobility group box 1 (HMGB1) has been proven to have a important role in drug resistance via upregulation of autophagy after chemotherapy treatment in acute leukemia. However, the mechanism how extracellular HMGB1 acts on AL cells and leads to chemoresistance remains elusive. Method CCK8 was used to examine the toxicity of chemotherapeutic drug. Elisa was performed to detect the release of HMGB1. Western blot and mRFP-GFP-LC3 adenoviral particles as well as transmission electron microscopy were used to detect the autophagy flux. Western blot and flow cytometry were applied to evaluate the apoptosis. qPCR and western blot were conducted to detect the expression of drug efflux protein. Lentivirus infection was applied to knock down RAGE. In addition, T-ALL NOD/SCID mice xenograft model was used to observe the effect of inhibiting HMGB1/RAGE axis. Results We found that extracellular HMGB1 do upregulate autophagy and in the meantime downregulate apoptosis, primarily through interaction with receptor for advanced glycation end products (RAGE). Suppression of RAGE by RNA interference alleviated the level of autophagy and enhanced apoptosis. What’s more, HMGB1/RAGE induced autophagy was associated with the activation of ERK1/2 and decreased phosphorylation of mammalian target of rapamycin (mTOR), while HMGB1/RAGE limited apoptosis in a Bcl-2-regulated way mediated by P53. On the other hand, we found that HMGB1/RAGE activated the NF-κB pathway and promoted the expression of P-glycation protein (P-gp) as well as multidrug resistance-associated protein (MRP), both are ATP-binding cassette transporters. In vivo experiment, we found that blocking HMGB1/RAGE axis do have a mild pathological condition and a better survival in T-ALL mice. Conclusion HMGB1/RAGE have a important role in drug resistance after chemotherapy treatment, mainly by regulating autophagy and apoptosis as well as promoting the expression of drug efflux protein such as P-gp and MRP. HMGB1/RAGE might be a promising target to cure AL, especially for those met with relapse and refractory.