title: MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients.
abstract: Although imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), 25-30% patients do not respond or relapse after initial response. Imatinib uptake into targeted cells is crucial for its molecular response and clinical effectiveness. The organic cation transporter 1 (OCT1) has been proposed to be responsible for this process, but its relevance has been discussed controversially in recent times. Here we found that the multidrug and toxin extrusion protein 1 (MATE1) transports imatinib with a manifold higher affinity. MATE1 mainly mediates the cellular uptake of imatinib into targeted cells and thereby controls the intracellular effectiveness of imatinib. Importantly, MATE1 but not OCT1 expression is reduced in total bone marrow cells of imatinib-non-responding CML patients compared with imatinib-responding patients, indicating that MATE1 but not OCT1 determines the therapeutic success of imatinib. We thus propose that imatinib non-responders could be identified early before starting therapy by measuring MATE1 expression levels.
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Harrach
authors.affiliation: Experimental Nephrology, Medizinische Klinik D, University Hospital Münster, Münster, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schmidt-Lauber
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Pap
authors.affiliation: Molecular Nephrology, Department of Internal Medicine D, University Hospital Münster, Münster, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Pavenstädt
authors.affiliation: Experimental Nephrology, Medizinische Klinik D, University Hospital Münster, Münster, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schlatter
authors.affiliation: Department of Medicine A, University Hospital Münster, Münster, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Department of Medicine A, University Hospital Münster, Münster, Germany.
authors.forename: W E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Molecular Nephrology, Department of Internal Medicine D, University Hospital Münster, Münster, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Schulze
authors.affiliation: Clinic and Polyclinic of Internal Medicine IV, Hematology and Oncology, University Hospital Halle, Halle (Saale), Germany.
authors.forename: B
authors.initials: B
authors.lastname: Edemir
authors.affiliation: MLL Munich Leukemia Laboratory, München, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Jeromin
authors.affiliation: MLL Munich Leukemia Laboratory, München, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Experimental Nephrology, Medizinische Klinik D, University Hospital Münster, Münster, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Ciarimboli
authors.affiliation: Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.|Department of Orthopedic Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Bertrand
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference
chemical_list: D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D047428:Protein Kinase Inhibitors; C521869:SLC47A1 protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl