Role of RNA Methylation Defined in Drug Resistance by Leukemia Cells

Results of a recent study defined the roles of RNA 5-methylcytosine (RNA:m5C) and RNA:m5C methyltransferases (RCMTs) in the formation of discrete 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 activity via two mechanisms - at low doses, by inhibiting of DNA methyltransferase, causing 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 extent 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 in the March 21, 2018, online edition of the journal Nature Communications 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 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 was 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.

"This is the first study to demonstrate that RNA cytosine methylation and methyltransferases mediate cell lineage-associated drug-responsive chromatin structures in MDS and AML," said first author Dr. Jason Cheng, assistant professor of pathology at the University of Chicago. "This is a new area. Although a large number of RNA modifications have been identified in the past, the function and the clinical potential of those RNA modifications and their effects on gene regulation and chromatin organization remain largely unexplored."

"With the advent of modern molecular and imaging technologies, functional genomics will become a central platform to elucidate the function of genes, signal pathways and genetic networks, to determine the pathogenetic roles of gene mutations and provide powerful tools for better prognosis and more effective treatment for cancer/leukemia patients," said Dr. Cheng. "We are moving towards functional genomics through exploring the potential of using RNA epigenetics and chromatin structures as diagnostic tools and potential therapeutic targets in MDS/AML patients."

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