Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia.
Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia.
复制标题
在慢性粒细胞白血病小鼠模型中，造血干细胞中 P-糖蛋白表达的丧失并不能改善对伊马替尼的反应。
DOI：
10.1038/sj.leu.2403853
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发表时间：
2005
期刊：
影响因子：
11.4
通讯作者：
Sorrentino,BP
中科院分区：
文献类型：
--
作者：
Zong,Y;Zhou,S;Sorrentino,BP
Selective inhibition of the BCR/ABL tyrosine kinase by imatinib has become a first-line therapy for chronic myelogenous leukemia (CML). However, BCR/ABL-positive progenitors often persist despite treatment, and relapse associated with resistance to imatinib has been described in many patients with advanced disease. Drug efflux by P-glycoprotein (P-gp), as well as point mutations in BCR/ABL oncoprotein, has been implicated in the mechanism of resistance to imatinib. In this study, we established a murine transplantation model of CML-like myeloproliferative disease using Mdr1a/1b-null mice and analyzed the effects of loss of P-gp on resistance to imatinib. We found that mice transplanted with Mdr1a/1b-null bone marrow (BM) that had been transduced with a BCR/ABL retroviral vector displayed similar responses to imatinib, compared with those transplanted with BCR/ABL-transduced wild-type BM. In the absence of P-gp, the incidence and latency of disease in secondary recipients was not changed in imatinib-treated mice, relative to wild-type controls. Furthermore, K562 cells engineered to overexpress P-gp remained sensitive to imatinib-induced growth inhibition and cell death. Together, our findings suggest that P-gp expression in hematopoietic stem cells does not significantly contribute to imatinib resistance in CML.
