Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin(+) BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemo-resistance in vivo. Unlike bulk stroma, nestin(+) BMSC numbers are not reduced in AML, but their function changestosupportAMLcells, at the expenseofnon-mutatedhematopoieticstemcells (HSCs). Nestin(+) cell depletion delays leukemogenesis in primaryAMLmice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin(+) BMSCs support survival and chemotherapy relapse ofAMLthrough increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy. CONTEXT AND SIGNIFICANCE Several lines of evidence indicate that themicroenvironment plays a key role in leukemia development, chemoresistance, and, more recently, resistance to immunotherapy. Therefore, dissecting and targeting niche-driven mechanisms of resistance might provide key adjuvant therapies to eradicate leukemia. This study shows that BMSCs expressing the marker nestin directly support leukemia stem cell (LSC) survival and chemoresistance. Nestin(+) BMSCs increase energy production in LSCs through increased TCA cycle and oxidative phosphorylation (OXPHOS) and simultaneously provide LSCs with key antioxidant tools necessary to balance ROS levels during leukemogenesis and chemotherapy. GSH-dependent antioxidant pathways emerge as key players in the BMSC-LSC crosstalk and represent potential targets for adjuvant therapies in AML.