title: Stromal cell-mediated mitochondrial redox adaptation regulates drug resistance in childhood acute lymphoblastic leukemia.
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.
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Ashish
authors.initials: A
authors.lastname: Masurekar
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Bioinformatics Centre, Bose Institute, Kolkata, India.
authors.forename: Sohini
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Mass Spectrometry Service, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Griffiths
authors.affiliation: Mass Spectrometry Service, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Duncan
authors.initials: D
authors.lastname: Smith
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Seema
authors.initials: S
authors.lastname: Alexander
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Dempsey
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Catriona
authors.initials: C
authors.lastname: Parker
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Harrison
authors.affiliation: Applied Computational Biology and Bioinformatics Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Yaoyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Applied Computational Biology and Bioinformatics Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom.
authors.forename: Crispin
authors.initials: C
authors.lastname: Miller
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Di
authors.affiliation: Bioinformatics Centre, Bose Institute, Kolkata, India.
authors.forename: Zhumur
authors.initials: Z
authors.lastname: Ghosh
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.|Tata Translational Cancer Research Centre, Kolkata, India.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Children's Cancer Group, Institute of Cancer Science, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom.|Tata Translational Cancer Research Centre, Kolkata, India.
authors.forename: Vaskar
authors.initials: V
authors.lastname: Saha
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D014162:Transfection; D059016:Tumor Microenvironment / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species
keywords: ALL; drug resistance; metabolic stress response; oxidative stress; tumor microenvironment