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Determination of P-glycoprotein, MDR-related protein 1, breast cancer resistance protein, and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia

机译:急性髓性白血病白血病干细胞p-糖蛋白,mDR相关蛋白1,乳腺癌耐药蛋白及肺耐药蛋白表达的测定

摘要

Background: The most primitive leukemic precursor in acute myeloid leukemia (AML) is thought to be the leukemic stem cell (LSC), which retains the properties of self-renewal and high proliferative capacity and quiescence of the hematopoietic stem cell. LSC seems to be immunophenotypically distinct and more resistant to chemotherapy than the more committed blasts. Considering that the multidrug resistance (MDR) constitutive expression may be a barrier to therapy in AML, we have investigated whether various MDR transporters were differentially expressed at the protein level by different leukemic subsets. Methods: The relative expression of the drug-efflux pumps P-gp, MRP, LRP, and BCRP was evaluated by mean fluorescence index (MFI) and the Kolmogorov-Smirnov analysis (D values) in five leukemic subpopulations: CD34(+)CD38(-)CD123(+) (LSCs), CD34(+)CD38(+)CD123(-), CD34(+)CD38(+)CD123(+), CD34(+)CD38(+)CD123(-), and CD34(-) mature cells in 26 bone marrow samples of CD34(+) AML cases. Results: The comparison between the two more immature subsets (LSC versus CD34(+)CD38(-)CD123(-) cells) revealed a higher P-gp, MRP, and LRP expression in LSCs. The comparative analysis between LSCs and subsets of intermediate maturation (CD34(+)CD38(+)) demonstrated the higher BCRP expression in the LSCs. In addition, P-gp expression was also significantly higher in the LSC compared to CD34(+)CD38(+)CD123(-) subpopulation. Finally, the comparative analysis between LSC and the most mature subset (CD34(-)) revealed higher MRP and LRP and lower P-gp expression in the LSCs. Conclusions: Considering the cellular heterogeneity of AML, the higher MDR transporters expression at the most immature, self-renewable, and quiescent LSC population reinforces that MDR is one of the mechanisms responsible for treatment failure. (C) 2008 Clinical Cytometry Society.
机译:背景:急性髓性白血病(AML)中最原始的白血病前体被认为是白血病干细胞(LSC),它保留了造血干细胞的自我更新,高增殖能力和静止特性。 LSC似乎在免疫表型上是独特的,并且比更坚决的原始细胞更能抵抗化学疗法。考虑到多药抗性(MDR)组成型表达可能是AML治疗的障碍,我们研究了不同的白血病亚群是否在蛋白质水平上差异表达了多种MDR转运蛋白。方法:通过平均荧光指数(MFI)和Kolmogorov-Smirnov分析(D值)评估五个白血病亚群CD34(+)CD38中药物外排泵P-gp,MRP,LRP和BCRP的相对表达。 (-)CD123(+)(LSC),CD34(+)CD38(+)CD123(-),CD34(+)CD38(+)CD123(+),CD34(+)CD38(+)CD123(-),和CD34(-)成熟细胞在CD34(+)AML病例的26个骨髓样本中。结果:两个不成熟子集(LSC与CD34(+)CD38(-)CD123(-)细胞)之间的比较显示LSC中较高的P-gp,MRP和LRP表达。 LSC和中间成熟子集(CD34(+)CD38(+))之间的比较分析表明,在LSC中BCRP的表达较高。此外,与CD34(+)CD38(+)CD123(-)亚群相比,LSC中的P-gp表达也明显更高。最后,在LSC和最成熟的子集(CD34(-))之间的比较分析显示LSC中MRP和LRP较高,而P-gp表达较低。结论:考虑到AML的细胞异质性,在最不成熟,可自我更新和静止的LSC群体中较高的MDR转运蛋白表达增强了MDR是导致治疗失败的机制之一。 (C)2008临床细胞计数学会。

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