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

Burt, R; Dey, A; Aref, S; Aguiar, M; Akarca, A; Bailey, K; Day, W; ... Fielding, AK; + view all (2019) Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Blood , 134 (17) pp. 1415-1429. 10.1182/blood.2019001398. Green open access

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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.

Type: Article
Title: Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood.2019001398
Publisher version: https://doi.org/10.1182/blood.2019001398
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10081883
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