Brendel C, Scharenberg C, Dohse M, Robey R W, Bates S E, Shukla S, Ambudkar S V, Wang Y, Wennemuth G, Burchert A, Boudriot U, Neubauer A
Department of Hematology, Oncology and Immunology, Philipps-University Marburg, Baldingerstrasse, Marburg, Germany.
Leukemia. 2007 Jun;21(6):1267-75. doi: 10.1038/sj.leu.2404638. Epub 2007 Mar 22.
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 [(125)I] 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.
大多数接受酪氨酸激酶抑制剂（TKI）甲磺酸伊马替尼治疗的慢性期慢性髓性白血病（CML）患者对该药物保持持久反应。然而，大多数患者在停用伊马替尼后复发，晚期患者常出现耐药。由于CML被认为是一种造血干细胞癌症，据推测内在的保护机制导致患者复发。ATP结合盒转运蛋白ABCB1（多药耐药蛋白1；P-糖蛋白）和ABCG2在原始造血干细胞（HSCs）上高度表达，并已证明与TKIs相互作用。在此我们证明，伊马替尼和尼罗替尼（AMN107，一种新型的BCR-ABL氨基嘧啶抑制剂）对原代人及小鼠造血干细胞中ABCG2介导的Hoechst 33342染料外排具有剂量依赖性、可逆性抑制作用。ABCG2转导的K562细胞对伊马替尼和尼罗替尼介导的细胞死亡具有抗性，且对P-CRKL的下调具有抗性。此外，光亲和标记显示两种TKIs在底物结合位点与ABCG2相互作用，因为它们与[(125)I] IAAP的结合竞争，并且还刺激转运蛋白的ATP酶活性。因此，我们的证据表明ABC转运蛋白在原始造血干细胞和CML干细胞对TKI的耐药中起作用，并为如何在体内克服TKI耐药提供了理论依据。
