Expression of ABCC-type nucleotide exporters in blasts of adult acute myeloid leukemia: relation to long-term survival.
Expression of ABCC-type nucleotide exporters in blasts of adult acute myeloid leukemia: relation to long-term survival.
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DOI：
10.1158/1078-0432.ccr-08-0442
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发表时间：
2009-03-01
期刊：
影响因子：
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通讯作者：
Schaich M
中科院分区：
文献类型：
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作者：
Guo Y;Köck K;Ritter CA;Chen ZS;Grube M;Jedlitschky G;Illmer T;Ayres M;Beck JF;Siegmund W;Ehninger G;Gandhi V;Kroemer HK;Kruh GD;Schaich M
急性髓细胞白血病（AML）的成功治疗仍然是一个治疗挑战，高比例的患者患有持续性或复发性疾病。对药物疗法的抗性可从增加的药物输出和/或改变的细胞内信号传导发展。这两种机制都是由外排转运蛋白ABCC 4（MRP 4）、ABCC 5（MRP 5）和ABCC 11（MRP 8）介导的，它们参与内源性信号分子（例如，环腺苷3 '，5'-一磷酸和环鸟苷3 '，5'-一磷酸）和核苷类似物。核苷类似物阿糖胞苷（AraC）用于所有AML患者。通过实时逆转录-PCR分析研究了50例AML患者原始细胞样本中ABCC转运蛋白MRP 4、MRP 5和MRP 8的表达，并与临床结局指标相关。在MRP 8转染的LLC-PK 1细胞中分析了放射性标记的AraC的蓄积、AraC代谢物的转运和AraC的细胞毒性。回归分析显示，MRP 8高表达与4年生存率低相关（P < 0.03）。MRP 8转染的LLC-PK 1细胞积累了降低的细胞内水平的AraC（亲本载体转染的LLC-PK 1对照细胞的63%）以及AraC代谢物。此外，AraC单磷酸被富含MRP 8的膜囊泡转运（116 ± 6 pmol/mg/10分钟，对照囊泡为65 ± 13 pmol/mg/10分钟），MRP 8转染的细胞对AraC具有抗性。这些数据表明，MRP 8在AML母细胞中差异表达，MRP 8的表达可作为AML治疗结果的预测标志物，MRP 8的AraC代谢物外排是导致AML母细胞耐药的机制。
Successful treatment of acute myeloid leukemia (AML) remains a therapeutic challenge, with a high percentage of patients suffering from persistent or relapsed disease. Resistance to drug therapy can develop from increased drug export and/or altered intracellular signaling. Both mechanisms are mediated by the efflux transporters ABCC4 (MRP4), ABCC5 (MRP5), and ABCC11 (MRP8), which are involved in cellular efflux of endogenous signaling molecules (e.g., cyclic adenosine 3′, 5′-monophosphate and cyclic guanosine 3′,5′-monophosphate) and nucleoside analogues. The nucleoside analogue cytosine arabinoside (AraC) is administered to all patients with AML. Expression of ABCC transporters MRP4, MRP5, and MRP8 in blast samples from 50 AML patients was investigated by real-time reverse transcription-PCR analysis and correlated with clinical outcome measures. Accumulation of radiolabeled AraC, transport of AraC metabolites, and AraC cytotoxicity were analyzed in MRP8-transfected LLC-PK1 cells. Regression analysis revealed that high expression of MRP8 is associated with a low probability of overall survival assessed over 4 years (P < 0.03). MRP8-transfected LLC-PK1 cells accumulated reduced intracellular levels of AraC (63% of the parental vector-transfected LLC-PK1 control cells) as well as AraC metabolites. Furthermore, AraC monophosphate was transported by MRP8-enriched membrane vesicles (116 ± 6 versus 65 ± 13 pmol/mg/10 minutes by control vesicles), and MRP8-transfected cells were resistant to AraC. These data suggest that MRP8 is differentially expressed in AML blasts, that expression of MRP8 serves as a predictive marker for treatment outcome in AML, and that efflux of AraC metabolites by MRP8 is a mechanism that contributes to resistance of AML blasts.