title: Stromal control of cystine metabolism promotes cancer cell survival in chronic lymphocytic leukaemia.
abstract: Tissue stromal cells interact with leukaemia cells and profoundly affect their viability and drug sensitivity. Here we show a biochemical mechanism by which bone marrow stromal cells modulate the redox status of chronic lymphocytic leukaemia (CLL) cells and promote cellular survival and drug resistance. Primary CLL cells from patients exhibit a limited ability to transport cystine for glutathione (GSH) synthesis owing to a low expression level of Xc-transporter. In contrast, bone marrow stromal cells effectively import cystine and convert it to cysteine, which is then released into the microenvironment for uptake by CLL cells to promote GSH synthesis. The elevated level of GSH enhances leukaemia cell survival and protects them from drug-induced cytotoxicity. Furthermore, disabling this protective mechanism significantly sensitizes CLL cells to drug treatment in the stromal environment. This stromal-leukaemia interaction is critical for CLL cell survival and represents a key biochemical pathway for effectively targeting leukaemia cells to overcome drug resistance in vivo.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Wan
authors.initials: W
authors.lastname: Zhang
authors.forename: Dunyaporn
authors.initials: D
authors.lastname: Trachootham
authors.forename: Jinyun
authors.initials: J
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Helene
authors.initials: H
authors.lastname: Pelicano
authors.forename: Celia
authors.initials: C
authors.lastname: Garcia-Prieto
authors.forename: Weiqin
authors.initials: W
authors.lastname: Lu
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002450:Cell Communication; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D003553:Cystine / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005978:Glutathione / Q000096:biosynthesis*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology; D008970:Molecular Weight; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017382:Reactive Oxygen Species / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin; D003553:Cystine; D014740:Vidarabine; D005978:Glutathione; D003545:Cysteine; C024352:fludarabine