Targeting the autophagy in bone marrow stromal cells overcomes resistance to vorinostat in chronic lymphocytic leukemia

Background: The bone marrow microenvironment constitutes a sanctuary for leukemia cells. Recent evidence indicates that environment-mediated drug resistance arises from a reciprocal influence between tumor cells and the surrounding stroma. The present study aimed to investigate the effect of chronic lymphocytic leukemia (CLL) cells on the metabolism of bone marrow stroma, to determine the role of this metabolic change in the stroma in vorinostat resistance of CLL cells, and thus to assess a novel strategy to target stroma and achieve the maximum therapeutic effect of vorinostat. Methods: To evaluate this issue, we used freshly isolated CLL cells from peripheral blood samples of patients with CLL, and co-cultured them with bone marrow stromal cell lines to examine autophagy activity and metabolic changes in both CLL cells and stromal cells after vorinostat treatment. Results: The results demonstrated that CLL cells were under intrinsic oxidative stress which was further enhanced by vorinostat treatment, and released H ₂ O ₂ outside the cells. The adjacent stromal cells took up H ₂ O ₂ and drove autophagy, mitophagy and glycolysis, resulting in the local production of high-energy mitochondrial fuels, which were then taken up by CLL cells to be effectively utilized through mitochondrial oxidative phosphorylation to enable more ATP production. Notably, targeting autophagic stromal cells with autophagy inhibitor remarkably decreased stromal protection against vorinostat treatment in CLL cells. Conclusion: This study demonstrated that the stroma in the CLL microenvironment is abnormal and undergoes autophagy, and manipulation of autophagic stromal cells could serve as a novel promising strategy to circumvent stroma-mediated drug resistance in CLL cells.