Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital Shanghai 200233, China.
Cell Death Dis. 2017 Oct 12;8(10):e3126. doi: 10.1038/cddis.2017.526.
MYC proto-oncogene family including c-myc and n-myc (MYCN) are critical for normal cell development and tumorigenesis. Overexpression of c-myc causes acute erythroleukemia in vivo. However, the role of MYCN in acute erythroleukemia remains poorly understood. In this study, we found that the patients with erythroleukemia showed higher expression of MYCN than normal controls. In vitro experiments, knockdown of MYCN resulted in decreased cell proliferation, elevated autonomously cell apoptosis and increased P21-mediated cell senescence. On the contrary, overexpression of MYCN obviously promoted cell proliferation, and induced erythroid differentiation block and apoptosis resistance to cytotoxic agent. Further gene microarray and functional analysis revealed that EZH2 is a target of MYCN. Knockdown of MYCN inhibited the expression of EZH2, and then activated p21 expression through removal of H3K27me3 at the p21 promoter. Overexpression of ezh2 could antagonize the p21 activation caused by MYCN knockdown. In addition, Aurora inhibitor MLN8237 inhibited the proliferation of erythroleukemia cells through repression of MYCN/EZH2 axis, whereas it minimally affected the normal hematopoietic cells. In conclusion, MYCN contributes to the malignant characteristics of erythroleukemia through EZH2-meidated epigenetic repression of p21. MYCN may serve as a therapy target for the patients with acute erythroleukemia.
MYC 原癌基因家族，包括 c-myc 和 n-myc（MYCN），对于正常细胞的发育和肿瘤发生至关重要。c-myc 的过表达会导致体内急性红白血病。然而，MYCN 在急性红白血病中的作用仍知之甚少。在这项研究中，我们发现红白血病患者的 MYCN 表达高于正常对照。体外实验表明，敲低 MYCN 会导致细胞增殖减少、自主细胞凋亡增加和 P21 介导的细胞衰老增加。相反，过表达 MYCN 明显促进了细胞增殖，并诱导红系分化阻滞和对细胞毒剂的凋亡抵抗。进一步的基因微阵列和功能分析表明，EZH2 是 MYCN 的一个靶点。敲低 MYCN 抑制了 EZH2 的表达，然后通过去除 p21 启动子上的 H3K27me3 激活了 p21 的表达。过表达 ezh2 可以拮抗 MYCN 敲低引起的 p21 激活。此外，Aurora 抑制剂 MLN8237 通过抑制 MYCN/EZH2 轴抑制红白血病细胞的增殖，而对正常造血细胞的影响最小。总之，MYCN 通过 EZH2 介导的 p21 表观遗传抑制作用促进了红白血病的恶性特征。MYCN 可能成为急性红白血病患者的治疗靶点。
