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Activated Stromal Cells Transfer Mitochondria to Rescue Acute Lymphoblastic Leukaemia Cells from Oxidative Stress.

Richard Burt, Aditi Dey, Sarah Aref, Melanie Aguiar, Ayse Akarca, Katharine Bailey, William Day, Steven Hooper, Amy Kirkwood, Kristina Kirschner, SooWah Lee, Cristina Lo Celso, Jiten Manji, Marc R. Mansour, Teresa Marafioti, Rachel J. Mitchell, Robert C. Muirhead, Kenton Cheuk Yan Ng, Constandina Pospori, Ignazio Puccio, Krisztina Zuborne-Alapi, Erik Sahai and Adele K. Fielding

Key Points

  • BM-derived MSC 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 tunnelling nanotubes used for mitochondrial transfer.

Abstract

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

  • Submitted May 1, 2019.
  • Revision received August 20, 2019.
  • Accepted August 27, 2019.