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

• Published in: Blood Vol. 134; no. 17; pp. 1415 - 1429
• Main Authors: Burt, Richard, Dey, Aditi, Aref, Sarah, Aguiar, Melanie, Akarca, Ayse, Bailey, Katharine, Day, William, Hooper, Steven, Kirkwood, Amy, Kirschner, Kristina, Lee, Soo-Wah, Lo Celso, Cristina, Manji, Jiten, Mansour, Marc R., Marafioti, Teresa, Mitchell, Rachel J., Muirhead, Robert C., Cheuk Yan Ng, Kenton, Pospori, Constandina, Puccio, Ignazio, Zuborne-Alapi, Krisztina, Sahai, Erik, Fielding, Adele K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.10.2019; American Society of Hematology
• Subjects: Adult; Aged; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Cells, Cultured; Coculture Techniques; Cytarabine - pharmacology; Cytarabine - therapeutic use; Daunorubicin - pharmacology; Daunorubicin - therapeutic use; Female; Humans; Lymphoid Neoplasia; Male; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mice; Middle Aged; Mitochondria - drug effects; Mitochondria - metabolism; Oxidative Stress - drug effects; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019001398

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