ABCA3 as a possible cause of drug resistance in childhood acute myeloid leukemia
ABCA3 as a possible cause of drug resistance in childhood acute myeloid leukemia
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DOI：
10.1158/1078-0432.ccr-05-2587
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发表时间：
2006-07-15
影响因子：
11.5
通讯作者：
Efferth, Thomas
中科院分区：
文献类型：
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作者：
Steinbach, Daniel;Gillet, Jean-Pierre;Efferth, Thomas
背景：急性髓系白血病(AML)治疗中的一个主要问题是化疗药物的耐药性。多药耐药可由充当药物外排泵的三磷酸腺苷结合盒(ABC)转运体引起。实验设计：采用Taqman实时定量聚合酶链式反应和芯片技术，对38个ABC转运蛋白基因在儿童AML和健康骨髓中的表达进行分析。结果：利用基因芯片技术，我们发现了4种新的ABC转运蛋白：ABCA2、ABCA3、ABCB2和ABCC10。用实时荧光定量聚合酶链式反应检测42例AML患儿和18例健康儿童骨髓中这四种基因的过度表达。初治未缓解的21例患者中ABCA3的表达中位数是同期获得缓解的21例患者的3倍(P=0.023)。细胞系与多种不同的细胞抑制药物孵育后，ABCA3的表达上调。结论：ABCA2、ABCA3、ABCB2和ABCC10在儿童AML中的表达高于正常骨髓。ABCA3是最有可能导致耐药的转运蛋白。
Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters that function as drug efflux pumps. The majority of these proteins have not yet been examined in malignant diseases.Experimental Design: A newly developed microarray for the simultaneous quantification of 38 ABC transporter genes and Taqman real-time PCR was used to analyze the expression of ABC transporters in pediatric AML and healthy bone marrow. Small interfering RNA was used to verify the role of ABCA3 in drug resistance.Results: Using the microarray, we identified four new ABC transporters, which were overexpressed in many AML samples compared with healthy bone marrow: ABCA2, ABCA3, ABCB2, and ABCC10. The overexpression of these four genes was verified by real-time PCR in 42 samples from children with AML and 18 samples of healthy bone marrow. The median expression of ABCA3 was three times higher in 21 patients who had failed to achieve remission after the first course of chemotherapy than in a well-matched group of 21 patients who had achieved remission at this stage (P = 0.023). Incubation of cell lines with a number of different cytostatic drugs induced an up-regulation of ABCA3. Down-regulation of ABCA3 by small interfering RNA sensitized cells to doxorubicin.Conclusion: Our results show that ABCA2, ABCA3, ABCB2, and ABCC10 are overexpressed in childhood AML compared with healthy bone marrow. ABCA3 is the most likely transporter to cause drug resistance.