title: Image-based RNA interference screening reveals an individual dependence of acute lymphoblastic leukemia on stromal cysteine support.
abstract: Interactions with the bone marrow microenvironment are essential for leukemia survival and disease progression. We developed an imaging-based RNAi platform to identify protective cues from bone marrow derived mesenchymal stromal cells (MSC) that promote survival of primary acute lymphoblastic leukemia (ALL) cells. Using a candidate gene approach, we detected distinct responses of individual ALL cases to RNA interference with stromal targets. The strongest effects were observed when interfering with solute carrier family 3 member 2 (SLC3A2) expression, which forms the cystine transporter xc- when associated with SLC7A11. Import of cystine and metabolism to cysteine by stromal cells provides the limiting substrate to generate and maintain glutathione in ALL. This metabolic interaction reduces oxidative stress in ALL cells that depend on stromal xc-. Indeed, cysteine depletion using cysteine dioxygenase resulted in leukemia cell death. Thus, functional evaluation of intercellular interactions between leukemia cells and their microenvironment identifies a selective dependency of ALL cells on stromal metabolism for a relevant subgroup of cases, providing new opportunities to develop more personalized approaches to leukemia treatment.
authors.affiliation: Department of Pediatric Oncology, University Children's Hospital Zurich, Zurich, Switzerland. Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Boutter
authors.affiliation: Department of Pediatric Oncology, University Children's Hospital Zurich, Zurich, Switzerland. Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pediatric Oncology, University Children's Hospital Zurich, Zurich, Switzerland. Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Blerim
authors.initials: B
authors.lastname: Marovca
authors.affiliation: Institute of Molecular Biology, Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vonderheit
authors.affiliation: Department of Pediatric Oncology, University Children's Hospital Zurich, Zurich, Switzerland. Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grotzer
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollscheid
authors.affiliation: Synthetic and Systems Biology Unit, Biological Research Center, Szeged, Hungary. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: Peter
authors.initials: P
authors.lastname: Horvath
authors.affiliation: Department of Pediatric Oncology, University Children's Hospital Zurich, Zurich, Switzerland. Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Beat C
authors.initials: BC
authors.lastname: Bornhauser
authors.affiliation: Department of Pediatric Oncology, University Children's Hospital Zurich, Zurich, Switzerland. Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D016923:Cell Death; D002470:Cell Survival; D018920:Coculture Techniques; D003545:Cysteine / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology; D018384:Oxidative Stress; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D016207:Cytokines; D027282:Fusion Regulatory Protein 1, Heavy Chain; D017382:Reactive Oxygen Species; C545989:SLC3A2 protein, human; C118895:SLC7A11 protein, human; D003545:Cysteine