Inhibition of Atg7 Enhances Mesenchymal Stem Cells Regulates Energy Metabolism Coupling to Overcome Drug Resistance in Chronic Myeloid Leukemia

Abstract

Background and objective: A major drawback of tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is that primitive CML cells resistance and disease progression. Increasing researches have demonstrated that abnormal autophagy of Mesenchymal Stem Cells(MSC) becomes activated when cancer cells are subjected to chemotherapy, which is involved in the development of drug resistance. Therefore, study on the autophagy mechanism of leukemia and MSC serves as a new strategy in cancer treatment.

Methods: We analyzed the biological and metabolic effect of CML primary cells and cell lines co-cultured with MSC investigate whether autophagy regulate resistance in CML cells and whether Knockdown of Atg7 by CRISPR/Cas9 could affect the viabilities of drug-sensitive and drug-resistant CML cells.

Results: We detected more autophagosomes ,monocarboxylate transporter-1(MCT1) and lactic acid in CML-BC and patients with TKI-resistance significantly, and the mRNA of Atg7 showed a positive correlation with autophagosomes.In 1% oxygen concentration, Knockdown of Atg7 in KBM5-STI cells using CRISPR/Cas9 markedly decreased the level of MCT1 ,and increased apoptosis following treatment with Imatinib. Interestingly, co-cultured of KBM5-STI cells with MSC increased autophagy and chemoresistance exposed to Imatinib agents, and this was reversed following Atg7 knockdown decreased the level of MCT1 and lactic acid in MSCs. This effect was further enhanced by concomitant knockdown of Atg7 in both KBM5-STI and MSCs.

Conclusions: These findings strongly suggest that microenvironment autophagy regulates energy metabolism coupling and plays an important role in CML chemoresistance.Thus, the inhibition of Atg7 appears to be a valid strategy to enhance TKI-sensitivity, and it could indeed improve outcomes in CML therapy