Image-based RNA interference screening reveals an individual dependence of acute lymphoblastic leukemia on stromal cysteine support
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Jeannette Boutter1,8,*, Yun Huang1,8,*, Blerim Marovca1,8, Andreas Vonderheit2, Michael A. Grotzer1,8, Cornelia Eckert3, Gunnar Cario4, Bernd Wollscheid5, Peter Horvath6,7, Beat C. Bornhauser1,8,*, Jean-Pierre Bourquin1,8,*
1Department of Pediatric Oncology, University Children’s Hospital Zurich, Zurich, Switzerland
2Institute of Molecular Biology, Mainz, Germany
3Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Germany
4Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany
5Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
6Synthetic and Systems Biology Unit, Biological Research Center, Szeged, Hungary
7Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
8Children's Research Center (CRC), University Children's Hospital Zurich, Zurich, Switzerland
*These authors contributed equally to this work
Jean-Pierre Bourquin, email: [email protected]
Keywords: acute lymphoblastic leukemia, bone marrow stroma, microenvironment, oxidative stress, RNAi screen
Received: September 02, 2014 Accepted: October 03, 2014 Published: November 01, 2014
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.
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