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Sensitivity and Resistance to Therapy

Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells

Abstract

The majority of chronic phase chronic myeloid leukemia (CML) patients treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate maintain durable responses to the drug. However, most patients relapse after withdrawal of imatinib and advanced stage patients often develop drug resistance. As CML is considered a hematopoietic stem cell cancer, it has been postulated that inherent protective mechanisms lead to relapse in patients. The ATP binding-cassette transporters ABCB1 (MDR-1; P-glycoprotein) and ABCG2 are highly expressed on primitive hematopoietic stem cells (HSCs) and have been shown to interact with TKIs. Herein we demonstrate a dose-dependent, reversible inhibition of ABCG2-mediated Hoechst 33342 dye efflux in primary human and murine HSC by both imatinib and nilotinib (AMN107), a novel aminopyrimidine inhibitor of BCR-ABL. ABCG2-transduced K562 cells were protected from imatinib and nilotinib-mediated cell death and from downregulation of P-CRKL. Moreover, photoaffinity labeling revealed interaction of both TKIs with ABCG2 at the substrate binding sites as they compete with the binding of [125I] IAAP and also stimulate the transporter's ATPase activity. Therefore, our evidence suggests for the role of ABC transporters in resistance to TKI on primitive HSCs and CML stem cells and provides a rationale how TKI resistance can be overcome in vivo.

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Acknowledgements

This work was supported by the José Carreras Leukemia Foundation R06-31 to Cornelia Brendel and R04-22f to Andreas Burchert, a grant from the german PE Kempkes Stiftung and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and DFG-SFB TR17 to Andreas Burchert and Andreas Neubauer. The kind gift of imatinib mesylate from Elisabeth Buchdunger and nilotinib by Paul Manley from Novartis, Basel, Switzerland, is highly appreciated. We also like to thank Hans-Peter Elsässer at the laboratory of Cell Biology, Marburg, for help with the liquid scintillation experiments. We thank Kathleen Stabla and Petra Roth for skilful technical assistance. In addition we appreciate the kind gift from Professor Yoshikazu Sugimoto (Tokyo, Japan) who provided the ABCG2-transfected K562 cell line. We would also like to thank Beverly Torok-Storb for critical reading of this paper.

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Brendel, C., Scharenberg, C., Dohse, M. et al. Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia 21, 1267–1275 (2007). https://doi.org/10.1038/sj.leu.2404638

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