RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia
RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia
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DOI：
10.1182/blood-2011-11-382226
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发表时间：
2012-05-31
期刊：
影响因子：
20.3
通讯作者：
Chan, Kenneth K.
中科院分区：
文献类型：
--
作者：
Aimiuwu, Josephine;Wang, Hongyan;Chan, Kenneth K.
5-氮杂胞苷（5-azaC）是一种被批准用于骨髓增生异常综合征的氮杂核苷。据信大约80%-90%的5-azaC被掺入RNA中，这破坏了核酸和蛋白质代谢，导致细胞凋亡。较小部分（10%-20%）的5-azaC通过转化为三磷酸地西他滨和随后的DNA掺入来抑制DNA甲基化和合成。然而，其确切的作用机制仍不清楚。核糖核苷酸还原酶（RR）是一种高度调节的酶，包含2个亚基，RRM 1和RRM 2，提供DNA合成/修复所需的脱氧核糖核苷酸。在本研究中，我们首次发现5-azaC是白血病细胞系、小鼠模型和急性髓性白血病（AML）患者BM单核细胞中RRM 2的有效抑制剂。5-azaC诱导的RRM 2基因表达抑制涉及其直接RNA掺入和减弱的RRM 2 mRNA稳定性。因此，5-azaC引起脱氧核糖核苷酸池的主要扰动。我们在本文中还证明，RR介导的5-azaC向地西他滨的初始转化通过其自身的抑制而终止。总之，我们确定RRM 2作为AML中5-azaC的新分子靶点。我们的研究结果提供了一个更广泛的临床应用的基础，无论是单独或组合。（血。2012; 119（22）：5229-5238）
5-Azacytidine (5-azaC) is an azanucleoside approved for myelodysplastic syndrome. Approximately 80%-90% of 5-azaC is believed to be incorporated into RNA, which disrupts nucleic acid and protein metabolism leading to apoptosis. A smaller fraction (10%-20%) of 5-azaC inhibits DNA methylation and synthesis through conversion to decitabine triphosphate and subsequent DNA incorporation. However, its precise mechanism of action remains unclear. Ribonucleotide reductase (RR) is a highly regulated enzyme comprising 2 subunits, RRM1 and RRM2, that provides the deoxyribonucleotides required for DNA synthesis/repair. In the present study, we found for the first time that 5-azaC is a potent inhibitor of RRM2 in leukemia cell lines, in a mouse model, and in BM mononuclear cells from acute myeloid leukemia (AML) patients. 5-azaC-induced RRM2 gene expression inhibition involves its direct RNA incorporation and an attenuated RRM2 mRNA stability. Therefore, 5-azaC causes a major perturbation of deoxyribonucleotide pools. We also demonstrate herein that the initial RR-mediated 5-azaC conversion to decitabine is terminated through its own inhibition. In conclusion, we identify RRM2 as a novel molecular target of 5-azaC in AML. Our findings provide a basis for its more widespread clinical use either alone or in combination. (Blood. 2012; 119(22): 5229-5238)