Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress.

摘要: We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). used gene expression profiling, cytokine/chemokine quantification, flow cytometry, a variety of imaging techniques to show that MSCs, directly isolated from primary bone marrow specimens patients with ALL, frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, human MSCs MSC line HS27a both were activated de novo, when exposed reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) daunorubicin (DNR), phenomenon blocked by antioxidant N-acetyl cysteine. Chemotherapy-activated cells functionally evaluated coculture model ALL targets. Activated prevented therapy-induced apoptosis death targets, via mitochondrial transfer through tunneling nanotubes (TNTs). Reduction selective depletion or interference TNT formation microtubule inhibitors, such as vincristine (VCR), "rescue" function MSCs. Corticosteroids, also mainstay therapy, activation demonstrated AraC (but not VCR) induced transfer, mass increase murine NSG disseminated SEM cell-derived wherein CD19+ closely associated nestin+ after AraC, but other conditions. Our data propose readily clinically exploitable mechanism for improving treatment which traditional ROS-inducing chemotherapies are often ineffective at eradicating residual disease, despite efficiently killing bulk population.