Stromal cell-mediated mitochondrial redox adaptation regulates drug resistance in childhood acute lymphoblastic leukemia
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Jizhong Liu1, Ashish Masurekar1, Suzanne Johnson1, Sohini Chakraborty2, John Griffiths3, Duncan Smith3, Seema Alexander1, Clare Dempsey1, Catriona Parker1, Stephanie Harrison1, Yaoyong Li4, Crispin Miller4, Yujun Di1, Zhumur Ghosh2, Shekhar Krishnan1,5, Vaskar Saha1,5
1Children’s Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
2Bioinformatics Centre, Bose Institute, Kolkata, India
3Mass Spectrometry Service, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
4Applied Computational Biology and Bioinformatics Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom
5Tata Translational Cancer Research Centre, Kolkata, India
Vaskar Saha, e-mail: [email protected]
Keywords: tumor microenvironment, oxidative stress, metabolic stress response, drug resistance, ALL
Received: June 08, 2015 Accepted: October 02, 2015 Published: October 13, 2015
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.
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