Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up regulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase activity, which is particularly strong in DNR resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. In addition, analyzing gp91phox (CYBB-encoded Nox2 catalytic sub-unit) expression at the surface of leukemic blasts from 74 patients at diagnosis showed that NOX2 is generally more expressed and active in leukemic cells from the FAB M4/M5 subtypes compared to FAB M0 M2 ones. Using a gene expression based score we demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis, independent of the cytogenetic based risk classification, in AML patients.

中文翻译：

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NADPH氧化酶NOX2是急性髓性白血病化学耐药性不良预后的标志物

对化疗药物的耐药性是急性髓细胞性白血病（AML）治疗失败的主要原因。为了更好地表征化学抗药性的机制，我们首先鉴定了在对柔红霉素（DNR）或阿糖胞苷（Ara C）（用于诱导疗法的主要药物）耐药的AML细胞中其表达失调的基因。发现被激活的基因主要与免疫信号和炎症有关。其中，我们确定了NOX2 NAPDH氧化酶亚基基因（CYBB，CYBA，NCF1，NCF2，NCF4和RAC2）的强烈上调。随之而来的NADPH氧化酶活性的增加（在DNR抗性细胞中特别强）参与了对DNR的抗性的获得和/或维持。此外，分析诊断时来自74位患者的白血病母细胞表面的gp91phox（CYBB编码的Nox2催化亚基）表达表明，与FAB M0 M2相比，FAB M4 / M5亚型的白血病细胞中NOX2通常更具表达和活性。使用基于基因表达的评分，我们证明了高NOX2亚基基因表达是AML患者不良预后的标志物，与基于细胞遗传学的风险分类无关。