Université Pierre et Marie Curie, INSERM UMRs 872, Equipe 18, Centre de Recherche des Cordeliers, Paris, France.
Haematologica. 2011 Sep;96(9):1293-301. doi: 10.3324/haematol.2010.031823. Epub 2011 May 23.
A major issue in the treatment of acute myeloid leukemia is resistance to chemotherapeutic drugs. An increasing number of ATP-Binding-Cassette transporters have been demonstrated to cause resistance to cancer drugs. The aim of this study was to highlight the putative role of other ATP-Binding-Cassette transporters in primary chemoresistant acute myeloid leukemia.
In the first part of this study, using taqman custom arrays, we analyzed the relative expression levels of 49 ATP-Binding-Cassette genes in 51 patients divided into two extreme cohorts, one very sensitive and one very resistant to chemotherapy. In the second part of this study, we evaluated the prognostic impact, in a cohort of 281 patients, of ATP-Binding-Cassette genes selected in the first part of the study.
In the first part of the study, six genes (ATP-Binding-CassetteA2, ATP-Binding-CassetteB1, ATP-Binding-CassetteB6, ATP-Binding-CassettC13, ATP-Binding-CassetteG1, and ATP-Binding-CassetteG2) were significantly over-expressed in the resistant group compared with the sensitive group. In the second cohort, overexpression of 5 of these 6 ATP-Binding-Cassette genes was correlated with outcome in univariate analysis, and only the well-known ATP-Binding-CassetteB1 and G2, and the new ATP-Binding-CassetteG1 in multivariate analysis. Prognosis decreased remarkably with the number of these over-expressed ABC genes. Complete remission was achieved in 71%, 59%, 54%, and 0%, (P=0.0011) and resistance disease in 21%, 37%, 43%, and 100% (P<0.0001) of patients over-expressing 0, 1, 2, or 3, ABC genes, respectively. The number of ATP-Binding-Cassette genes expressed, among ATP-Binding-CassetteB1, G1, and G2, was the strongest prognostic factor correlated, in multivariate analysis, with achievement of complete remission (P=0.01), resistant disease (P=0.01), and overall survival (P=0.02).
Using expression profiling, we have emphasized the diversity of ATP-Binding-Cassette transporters that cooperate to promote chemoresistance rather than overexpression of single transporters and the putative role of new ATP-Binding-Cassette tranporters, such as ATP-Binding-CassetteG1. Modulation of these multiple transporters might be required to eradicate leukemic cells.
急性髓细胞性白血病治疗中的一个主要问题是对化疗药物的耐药性。越来越多的 ATP 结合盒转运蛋白已被证明导致癌症药物耐药。本研究的目的是强调其他 ATP 结合盒转运蛋白在原发性化疗耐药急性髓细胞性白血病中的假定作用。
在本研究的第一部分中，我们使用 taqman 定制阵列分析了 51 例患者中 49 个 ATP 结合盒基因的相对表达水平，这些患者分为两个极端队列，一个对化疗非常敏感，另一个对化疗非常耐药。在本研究的第二部分中，我们评估了在 281 例患者队列中，第一部分研究中选择的 ATP 结合盒基因的预后影响。
在研究的第一部分，与敏感组相比，耐药组有 6 个基因（ATP 结合盒 A2、ATP 结合盒 B1、ATP 结合盒 B6、ATP 结合盒 C13、ATP 结合盒 G1 和 ATP 结合盒 G2）的表达明显上调。在第二队列中，这 6 个 ATP 结合盒基因中的 5 个在单因素分析中与结果相关，只有众所周知的 ATP 结合盒 B1 和 G2 以及新的 ATP 结合盒 G1 在多因素分析中相关。这些过表达 ABC 基因的数量显著降低了预后。完全缓解率分别为 71%、59%、54%和 0%（P=0.0011），耐药疾病分别为 21%、37%、43%和 100%（P<0.0001），过表达 0、1、2 或 3 个 ABC 基因的患者。在多因素分析中，ATP 结合盒基因表达数量（包括 ATP 结合盒 B1、G1 和 G2）与完全缓解（P=0.01）、耐药疾病（P=0.01）和总生存（P=0.02）相关的最强预后因素。
通过表达谱分析，我们强调了合作促进化疗耐药的 ATP 结合盒转运蛋白的多样性，而不是单个转运蛋白的过表达，以及新的 ATP 结合盒转运蛋白（如 ATP 结合盒 G1）的假定作用。可能需要调节这些多种转运蛋白以根除白血病细胞。
