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

Burt, R. et al. (2019) Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukaemia cells from oxidative stress. Blood, 134(17), pp. 1415-1429. (doi: 10.1182/blood.2019001398) (PMID:31501154) (PMCID:PMC6856969)

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 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.

• Item Type: Articles
• Additional Information: RB was supported by the CRUK-UCL Centre Award/Clinical Training Award Cycle 2 [A20937] and a Lady Tata Memorial Trust International Award. The UKALL14 trial was funded by grant to AKF CRUK/09/006 from CRUK. The UKALL14 biobank was funded by grant C27995/A21019 to AKF and Anthony V. Moorman from CRUK.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kirschner, Dr Kristina
• Authors: Burt, R., Dey, A., Aref, S., Aguiar, M., Akarca, A., Bailey, K., Day, W., Hooper, S., Kirkwood, A., Kirschner, K., Lee, S., Lo Celso, C., Manji, J., Mansour, M. R., Marafioti, T., Mitchell, R. J., Muirhead, R. C., Ng, K. C. Y., Pospori, C., Puccio, I., Zuborne-Alapi, K., Sahai, E., and Fielding, A. K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• Publisher: American Society of Hematology
• ISSN: 0006-4971
• ISSN (Online): 1528-0020
• Published Online: 09 September 2019
• Copyright Holders: Copyright © 2019 by The American Society of Hematology
• First Published: First published in Blood 134(17):1415-1429
• Publisher Policy: Reproduced in accordance with the publisher copyright policy