INSERM U753, Insitut Gustave Roussy, Villejuif, France;
Institut Jacques Monod, Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Paris, France;
Blood. 2014 Jun 5;123(23):3585-95. doi: 10.1182/blood-2013-11-536219. Epub 2014 Mar 27.
Cytarabine (cytosine arabinoside) is one of the most effective drugs for the treatment of patients diagnosed with acute myeloid leukemia (AML). Despite its efficiency against AML cells, the emergence of drug resistance due to prolonged chemotherapy in most patients is still a major obstacle. Several studies have shown that drug resistance mechanisms alter the sensitivity of leukemia cells to immune system effector cells. To investigate this phenomenon, parental acute myeloid cell lines, HL-60 and KG-1, were continuously exposed to increasing doses of cytarabine in order to establish equivalent resistant cell lines, HL-60(R) and KG-1(R). Our data indicate that cytarabine-resistant cells are more susceptible to natural killer (NK)-mediated cell lysis as compared with parental cytarabine-sensitive cells. The increased susceptibility correlates with the induction of UL-16 binding proteins (ULBP) 1/2/3 and NK group 2, member D (NKG2D) ligands on target cells by a mechanism involving c-Myc induction. More importantly, chromatin immunoprecipitation assay revealed that ULBP1/3 are direct targets of c-Myc. Using drug-resistant primary AML blasts as target cells, inhibition of c-Myc resulted in decreased expression of NKG2D ligands and the subsequent impairment of NK cell lysis. This study provides for the first time, the c-Myc dependent regulation of NKG2D ligands in AML.
阿糖胞苷（胞嘧啶阿拉伯糖苷）是治疗急性髓系白血病（AML）患者最有效的药物之一。尽管它对 AML 细胞有效，但由于大多数患者长期化疗，耐药性的出现仍然是一个主要障碍。多项研究表明，耐药机制改变了白血病细胞对免疫系统效应细胞的敏感性。为了研究这一现象，亲本急性髓系细胞系 HL-60 和 KG-1 连续暴露于递增剂量的阿糖胞苷中，以建立等效的耐药细胞系 HL-60(R) 和 KG-1(R)。我们的数据表明，与亲本阿糖胞苷敏感细胞相比，阿糖胞苷耐药细胞对自然杀伤（NK）介导的细胞裂解更为敏感。这种增加的敏感性与靶细胞上 UL-16 结合蛋白（ULBP）1/2/3 和 NK 组 2，成员 D（NKG2D）配体的诱导相关，该机制涉及 c-Myc 诱导。更重要的是，染色质免疫沉淀分析显示 ULBP1/3 是 c-Myc 的直接靶标。使用耐药性原发性 AML 原始细胞作为靶细胞，抑制 c-Myc 导致 NKG2D 配体的表达减少，随后 NK 细胞裂解受损。这项研究首次提供了 c-Myc 依赖性调节 AML 中 NKG2D 配体的证据。
