Wang Ruiheng, Xie Shufeng, Zhu Shouhai, Sun Yong, Shi Bowen, Li Dan, Kang Ting, Wang Yuanli, Xu Zhenshu, Liu Han
Shanghai Institute of Hematology, State Key laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Discov. 2022 Apr 8;8(1):180. doi: 10.1038/s41420-022-00989-4.
Oncogene-induced tumorigenesis results in the variation of epigenetic modifications, and in addition to promoting cell immortalization, cancer cells undergo more intense cellular stress than normal cells and depend on other support genes for survival. Chromosomal translocations of mixed-lineage leukemia (MLL) induce aggressive leukemias with an inferior prognosis. Unfortunately, most MLL-rearranged (MLL-r) leukemias are resistant to conventional chemotherapies. Here, we showed that hydroxyurea (HU) could kill MLL-r acute myeloid leukemia (AML) cells through the necroptosis process. HU target these cells by matrix metallopeptidase 2 (MMP2) deficiency rather than subordinate ribonucleotide reductase regulatory subunit M2 (RRM2) inhibition, where MLL directly regulates MMP2 expression and is decreased in most MLL-r AMLs. Moreover, iron chelation of HU is also indispensable for inducing cell stress, and MMP2 is the support factor to protect cells from death. Our preliminary study indicates that MMP2 might play a role in the nonsense-mediated mRNA decay pathway that prevents activation of unfolding protein response under innocuous endoplasmic reticulum stress. Hence, these results reveal a possible strategy of HU application in MLL-r AML treatment and shed new light upon HU repurposing.
致癌基因诱导的肿瘤发生会导致表观遗传修饰的变化，除了促进细胞永生化外，癌细胞比正常细胞承受更强烈的细胞应激，并且依赖其他支持基因来生存。混合谱系白血病（MLL）的染色体易位会诱发侵袭性白血病，预后较差。不幸的是，大多数MLL重排（MLL-r）白血病对传统化疗耐药。在此，我们表明羟基脲（HU）可通过坏死性凋亡过程杀死MLL-r急性髓系白血病（AML）细胞。HU通过基质金属肽酶2（MMP2）缺陷而非通过抑制次要的核糖核苷酸还原酶调节亚基M2（RRM2）来靶向这些细胞，其中MLL直接调节MMP2表达，且在大多数MLL-r AML中MMP2表达降低。此外，HU的铁螯合作用对于诱导细胞应激也是必不可少的，并且MMP2是保护细胞免于死亡的支持因子。我们的初步研究表明，MMP2可能在无义介导的mRNA衰变途径中发挥作用，该途径可防止在内质网应激无害的情况下激活未折叠蛋白反应。因此，这些结果揭示了HU在MLL-r AML治疗中的一种可能应用策略，并为HU的重新利用提供了新的思路。
