Metabolic Reprogramming In Acute Myeloid Leukemia Cells By Mesenchymal Stromal Cell-Derived Exosomes Induces Chemoresistance

Mesenchymal stromal cells play an important role in acute myeloid leukemia (AML) development. Altered cellular metabolism supports AML cells9 survival in multiple aspects, such as drug resistance. Here, we demonstrate the role of MSC-derived exosomes in metabolic regulation of AML cells, and put forward a combinatorial strategy to sensitize AML cells to chemodrugs. Exosomes secreted by MSCs can reprogram the metabolic machinery following their internalization by AML cells. Through 13C tracing experiments and flux analysis, we elucidate that MSC-derived exosomes enhance oxidative phosphorylation and glutamine9s entry into TCA cycle, which replenish the pool of carbon sources in mitochondria. Further, our work shows that inhibiting the interactions between MSCs and AML cells by targeting the metabolic regulation exerted by MSC-derived exosomes sensitizes AML cells to chemodrugs. Taken together, our work reveals a novel role of the TME in regulating the metabolic adaptation in AML cells and uncovers the improved strategy for AML therapy. Citation Format: Hongyun Zhao, Abhinav Achreja, Ziwen Zhu, Ahmed N. Rawi, Marina Konopleva, Michael Andreeff, Deepak Nagrath. Metabolic reprogramming in acute myeloid leukemia cells by mesenchymal stromal cell-derived exosomes induces chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4323. doi:10.1158/1538-7445.AM2017-4323