Role of RNA Methylation elucidate in Drug Resistance by Leukemia Cells

Results of a current study elucidate the roles of RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) in the formation of detached chromatin structures that modulate 5-Azacitidine (5-AZA) response or resistance in leukemia cells.Azacitidine is a chemical analogue of the nucleoside cytidine, which is present in DNA and RNA. It is thought to have anticancer stir via two mechanisms – at low doses, by inhibiting of DNA methyltransferase, provoke hypomethylation of DNA, and at high doses, by its direct cytotoxicity to abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA, resulting in cell death. Azacitidine is a ribonucleoside, so it is incorporated into RNA to a larger range than into DNA. Azacitidine’s incorporation into RNA leads to the disassembly of polyribosomes, defective methylation, and acceptor function of transfer RNA, and inhibition of the production of proteins.
Investigators at the University of Chicago Medical Center (IL, USA) reported that RCMTs interacted with different partners to form distinct complexes and active chromatin structures at nascent RNA in 5-AZA-sensitive leukemia cells (ASLCs) vs. 5-AZA-resistant leukemia cells (ARLCs). Such chromatin structures were important for the differential response or resistance to 5-AZA and survival of the leukemia cells. Based on this data, the investigators proposed a working model in which distinct RNA:m5C/RCMT-mediated chromatin structures were formed in ASLCs vs. the ARLCs. A significant increase in RNA:m5C and RCMT-associated active chromatin were observed in clinical 5-AZA-resistant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) specimens, supporting the importance and clinical relevance of the working model.