Stromal cell-mediated mitochondrial redox adaptation regulates drug resistance in childhood acute lymphoblastic leukemia

Liu, J. et al. (2015) Stromal cell-mediated mitochondrial redox adaptation regulates drug resistance in childhood acute lymphoblastic leukemia. Oncotarget, 6(40), pp. 43048-43064. (doi: 10.18632/oncotarget.5528) (PMID:26474278) (PMCID:PMC4767490)

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Abstract

Despite the high cure rates in childhood acute lymphoblastic leukemia (ALL), relapsed ALL remains a significant clinical problem. Genetic heterogeneity does not adequately explain variations in response to therapy. The chemoprotective tumor microenvironment may additionally contribute to disease recurrence. This study identifies metabolic reprogramming of leukemic cells by bone marrow stromal cells (BMSC) as a putative mechanism of drug resistance. In a BMSC-extracellular matrix culture model, BMSC produced chemoprotective soluble factors and facilitated the emergence of a reversible multidrug resistant phenotype in ALL cells. BMSC environment induced a mitochondrial calcium influx leading to increased reactive oxygen species (ROS) levels in ALL cells. In response to this oxidative stress, drug resistant cells underwent a redox adaptation process, characterized by a decrease in ROS levels and mitochondrial membrane potential with an upregulation of antioxidant production and MCL-1 expression. Similar expanded subpopulations of low ROS expressing and drug resistant cells were identified in pre-treatment bone marrow samples from ALL patients with slower response to therapy. This suggests that the bone marrow microenvironment induces a redox adaptation in ALL subclones that protects against cytotoxic stress and potentially gives rise to minimal residual disease. Targeting metabolic remodeling by inhibiting antioxidant production and antiapoptosis was able to overcome drug resistance. Thus metabolic plasticity in leukemic cell response to environmental factors contributes to chemoresistance and disease recurrence. Adjunctive strategies targeting such processes have the potential to overcome therapeutic failure in ALL.

Item Type:Articles
Additional Information:This study was supported by grants from Cancer Research UK and Leukaemia Lymphoma Research Fund to Vaskar Saha.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Miller, Professor Crispin
Authors: Liu, J., Masurekar, A., Johnson, S., Chakraborty, S., Griffiths, J., Smith, D., Alexander, S., Dempsey, C., Parker, C., Harrison, S., Li, Y., Miller, C., Di, Y., Ghosh, Z., Krishnan, S., and Saha, V.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Oncotarget
ISSN:1949-2553
ISSN (Online):1949-2553

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