c-Myc plays part in drug resistance mediated by bone marrow stromal cells in acute myeloid leukemia

Acute myeloid leukemia (AML) is a malignant and aggressive disease not sensitive to chemotherapy. The dynamic interaction between AML cells and bone marrow (BM) microenvironment plays a critical role in response of this disease to chemotherapy. It is reported that mesenchymal stromal cells (MSC) are essential component of bone marrow microenvironment which affects the survival of AML cells. The aim of our research is to elucidate the mechanism of drug resistance of AML cells associated with MSC. We found that adhesion of AML cell lines U937, KG1 a and primary AML cells to MSC inhibited cytotoxic drug-induced apoptosis. Western blot showed that c-Myc of AML cells cocultured with stroma was up-regulated. Treatment with 10058-F4, a small molecule inhibitor of MYC-MAX heterodimerization, or c-Myc siRNA significantly induced apoptosis. Western blot analysis further showed that inhibition of c-Myc induced expression of caspases-3, cleavage of PARP and reduced expression of Bc1-2, Bc1-xL and vascular endothelial growth factor (VEGF). Thus, we conclude that MSCs protected leukemia cells from apoptosis, at least in part, through c-Myc dependent mechanisms, and that c-Myc contributed to microenvironment-mediated drug resistance in AML. In summary, we declared that c-Myc is a potential therapeutic target for overcoming drug resistance in AML. (C) 2014 Elsevier Ltd. All rights reserved.

急性髓系白血病（AML）是一种对化疗不敏感的恶性侵袭性疾病。AML细胞与骨髓（BM）微环境之间的动态相互作用在该疾病对化疗的反应中起着关键作用。据报道，间充质基质细胞（MSC）是骨髓微环境的重要组成部分，它影响AML细胞的存活。我们的研究目的是阐明与MSC相关的AML细胞耐药机制。我们发现AML细胞系U937、KG1a以及原代AML细胞与MSC的黏附抑制了细胞毒性药物诱导的细胞凋亡。蛋白质印迹法显示与基质共培养的AML细胞的c - Myc上调。用10058 - F4（一种MYC - MAX异二聚化的小分子抑制剂）或c - Myc小干扰RNA处理显著诱导细胞凋亡。蛋白质印迹分析进一步显示，抑制c - Myc可诱导半胱天冬酶 - 3的表达、多聚ADP核糖聚合酶（PARP）的裂解，并降低Bcl - 2、Bcl - xL和血管内皮生长因子（VEGF）的表达。因此，我们得出结论，MSC至少部分通过c - Myc依赖机制保护白血病细胞免于凋亡，并且c - Myc促成了AML中微环境介导的耐药性。总之，我们宣称c - Myc是克服AML耐药性的一个潜在治疗靶点。（C）2014爱思唯尔有限公司。保留所有权利。