RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia

Josephine Aimiuwu, Hongyan Wang, Ping Chen, Zhiliang Xie, Jiang Wang, Shujun Liu, Rebecca Klisovic, Alice Mims, William Blum, Guido Marcucci, Kenneth K. Chan

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5229-5238
Number of pages10
JournalBlood
Volume119
Issue number22
DOIs
StatePublished - Jun 5 2012
Externally publishedYes

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