Chemotherapy resistance is the main cause of treatment failure in acute myeloid leukemia (AML) and has been related to ATP-binding cassette (ABC) transporter activity. However, the links between ABC activity, immunophenotype, and molecular AML parameters have been poorly evaluated. Moreover, the prognostic value of ABC activity, when compared to new molecular markers, is unknown. Here we investigated the links between ABC activity, as evaluated by JC-1 +/- cyclosporine A (CsA) assay, and immunophenotypic, cytogenetic, molecular, and targeted next generation sequencing features in 361 AML patients. High ABC activity was found in 164 patients and was significantly associated with less proliferating disease, an immature immunophenotype (expression of CD34, HLA-DR, CD117, CD13), and gene mutations defining AML as belonging to secondary-type ontogenic groups. Low ABC activity was associated with more mature myeloid differentiation (CD34-, cyMPO+, CD15+, CD33+) or monocytic commitment (CD64+, CD4+weak, CD14+), with NPM1 mutations, KMT2A rearrangements, and core-binding factor gene fusions, hallmarks of the de novotype AML ontogeny. ABC activity was one of the major factors we identified using a random forest model for early prediction of AML ontogeny. In the 230 patients evaluated at diagnosis and intensively treated, high ABC activity was a predictive factor for primary resistance, and in multivariate analysis including full molecular data, an independent factor for event-freesurvival (p=0.0370). JC-1 +/- CsA assay could be used at diagnosis to predict AML ontogeny and to complete prognosis evaluation in addition to new molecular markers.

中文翻译：

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ATP 结合盒转运蛋白活性对成人急性髓性白血病的临床和生物学影响。

化疗耐药是急性髓性白血病 (AML) 治疗失败的主要原因，并且与 ATP 结合盒 (ABC) 转运体活性有关。然而，ABC 活性、免疫表型和分子 AML 参数之间的联系尚未得到很好的评估。此外，与新分子标记相比，ABC 活性的预后价值尚不清楚。在这里，我们调查了 ABC 活性（通过 JC-1 +/- 环孢菌素 A (CsA) 测定评估）与 361 名 AML 患者的免疫表型、细胞遗传学、分子和靶向下一代测序特征之间的联系。在 164 名患者中发现高 ABC 活性，并且与增殖较少的疾病、不成熟的免疫表型（CD34、HLA-DR、CD117、CD13 的表达）显着相关，和基因突变定义 AML 属于二级类型的个体发生组。低 ABC 活性与更成熟的骨髓分化（CD34-、cyMPO+、CD15+、CD33+）或单核细胞定型（CD64+、CD4+弱、CD14+）相关，具有 NPM1 突变、KMT2A 重排和核心结合因子基因融合，标志de novotype AML 个体发育。ABC 活动是我们使用随机森林模型确定的主要因素之一，用于早期预测 AML 个体发育。在 230 名诊断时接受评估并接受强化治疗的患者中，高 ABC 活性是原发性耐药的预测因素，在包括全分子数据的多变量分析中，是无事件生存的独立因素 (p=0.0370)。