MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients
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MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients. / Harrach, S; Schmidt-Lauber, C; Pap, T; Pavenstädt, H; Schlatter, E; Schmidt, E; Berdel, W E; Schulze, U; Edemir, B; Jeromin, S; Haferlach, T; Ciarimboli, G; Bertrand, J.
in: BLOOD CANCER J, Jahrgang 6, Nr. 9, 16.09.2016, S. e470.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients
AU - Harrach, S
AU - Schmidt-Lauber, C
AU - Pap, T
AU - Pavenstädt, H
AU - Schlatter, E
AU - Schmidt, E
AU - Berdel, W E
AU - Schulze, U
AU - Edemir, B
AU - Jeromin, S
AU - Haferlach, T
AU - Ciarimboli, G
AU - Bertrand, J
PY - 2016/9/16
Y1 - 2016/9/16
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Antineoplastic Agents/pharmacology
KW - Cell Line, Tumor
KW - Drug Resistance, Neoplasm
KW - Female
KW - Fusion Proteins, bcr-abl/genetics
KW - Gene Expression
KW - Gene Knockdown Techniques
KW - Humans
KW - Imatinib Mesylate/pharmacology
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
KW - Male
KW - Middle Aged
KW - Organic Cation Transport Proteins/genetics
KW - Organic Cation Transporter 1/genetics
KW - Protein Kinase Inhibitors/pharmacology
KW - RNA Interference
U2 - 10.1038/bcj.2016.79
DO - 10.1038/bcj.2016.79
M3 - SCORING: Journal article
C2 - 27635733
VL - 6
SP - e470
JO - BLOOD CANCER J
JF - BLOOD CANCER J
SN - 2044-5385
IS - 9
ER -