Ding Lu, Zhang Wan, Yang Lili, Pelicano Helene, Zhou Kaiwen, Yin Ran, Huang Ruibin, Zeng Junyi
Department of Leukemia, The First Affiliated Hospital of Nanchang University, Nanchang, China,
School of Basic Medical Sciences, Nanchang University, Nanchang, China.
Onco Targets Ther. 2018 Aug 24;11:5151-5170. doi: 10.2147/OTT.S170392. eCollection 2018.
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.
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.
The results demonstrated that CLL cells were under intrinsic oxidative stress which was further enhanced by vorinostat treatment, and released HO outside the cells. The adjacent stromal cells took up HO 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.
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.
骨髓微环境构成白血病细胞的庇护所。最近的证据表明，环境介导的耐药性源于肿瘤细胞与周围基质之间的相互影响。本研究旨在探讨慢性淋巴细胞白血病（CLL）细胞对骨髓基质代谢的影响，确定这种基质代谢变化在CLL细胞对伏立诺他耐药中的作用，从而评估一种靶向基质并实现伏立诺他最大治疗效果的新策略。
为评估此问题，我们使用从CLL患者外周血样本中新鲜分离的CLL细胞，并将其与骨髓基质细胞系共培养，以检测伏立诺他治疗后CLL细胞和基质细胞中的自噬活性及代谢变化。
结果表明，CLL细胞处于内在氧化应激状态，伏立诺他治疗进一步增强了这种应激，并使细胞外释放HO。相邻的基质细胞摄取HO并驱动自噬、线粒体自噬和糖酵解，导致局部产生高能线粒体燃料，然后这些燃料被CLL细胞摄取，通过线粒体氧化磷酸化有效利用，从而产生更多ATP。值得注意的是，用自噬抑制剂靶向自噬性基质细胞可显著降低基质对CLL细胞伏立诺他治疗的保护作用。
本研究表明，CLL微环境中的基质异常并发生自噬，对自噬性基质细胞的调控可能是一种有前景的新策略，可规避基质介导的CLL细胞耐药性。
