van den Heuvel-Eibrink M M, Wiemer E A C, Prins A, Meijerink J P P, Vossebeld P J M, van der Holt B, Pieters R, Sonneveld P
Department of Hematology, University Hospital, Erasmus University, Rotterdam, The Netherlands.
Leukemia. 2002 May;16(5):833-9. doi: 10.1038/sj.leu.2402496.
Expression of the multidrug resistance proteins P-glycoprotein, encoded by the MDR1 gene, multidrug resistance-associated protein (MRP1) and the lung resistance-related protein or major vault protein (LRP/MVP) is associated with clinical resistance to chemotherapy in acute myeloid leukemia (AML). Recently, the breast cancer-resistant protein (BCRP), the equivalent of mitoxantrone-resistant protein (MXR) or placental ABC transporter (ABCP), was described in AML. We investigated MDR1, MRP1, LRP/MVP and BCRP mRNA expression simultaneously in 20 paired clinical AML samples from diagnosis and relapse or refractory disease, using quantitative Taqman analysis. In addition, standard assays for P-glycoprotein expression and function were performed. BCRP was the only resistance protein that was expressed at a significantly higher RNA level (median 1.7-fold, P = 0.04) at relapsed/refractory state as compared to diagnosis. In contrast, LRP/MVP mRNA expression decreased as disease evolved (P = 0.02), whereas MDR1 and MRP1 mRNA levels were not different at relapse as compared to diagnosis. Also, at the protein level no difference of MDR1 between diagnosis and relapse was found. A significant co-expression of BCRP and MDR1 was found at diagnosis (r = 0.47, P = 0.04). The present results suggest that BCRP, but not MDR1, MRP1 or LRP/MVP is associated with clinical resistant disease in AML.
由多药耐药基因1（MDR1）编码的多药耐药蛋白P-糖蛋白、多药耐药相关蛋白1（MRP1）以及肺耐药相关蛋白或主要穹窿蛋白（LRP/MVP）的表达与急性髓系白血病（AML）患者对化疗的临床耐药相关。最近，在AML中发现了乳腺癌耐药蛋白（BCRP），它等同于米托蒽醌耐药蛋白（MXR）或胎盘ABC转运蛋白（ABCP）。我们采用定量Taqman分析法，同时检测了20对临床AML样本（分别来自诊断时以及复发或难治性疾病阶段）中MDR1、MRP1、LRP/MVP和BCRP的mRNA表达。此外，还进行了P-糖蛋白表达和功能的标准检测。与诊断时相比，BCRP是唯一在复发/难治状态下RNA水平显著升高（中位数升高1.7倍，P = 0.04）的耐药蛋白。相反，随着疾病进展，LRP/MVP的mRNA表达下降（P = 0.02），而MDR1和MRP1的mRNA水平在复发时与诊断时相比没有差异。同样，在蛋白水平上，未发现诊断时和复发时MDR1有差异。在诊断时发现BCRP和MDR1存在显著的共表达（r = 0.47，P = 0.04）。目前的结果表明，在AML中，与临床耐药疾病相关的是BCRP，而非MDR1、MRP1或LRP/MVP。
