How Azanucleosides Affect Myeloid Cell Fate

Abstract

The azanucleosides decitabine and azacytidine are used widely in the treatment of myeloid neoplasia and increasingly in the context of combination therapies. Although they were long regarded as being largely interchangeable in their function as hypomethylating agents, the azanucleosides actually have different mechanisms of action; decitabine interferes primarily with the methylation of DNA and azacytidine with that of RNA. Here, we examine the role of DNA methylation in the lineage commitment of stem cells during normal hematopoiesis and consider how mutations in epigenetic regulators such as DNMT3A and TET2 can lead to clonal expansion and subsequent neoplastic progression. We also consider why the efficacy of azanucleoside treatment is not limited to neoplasias carrying mutations in epigenetic regulators. Finally, we summarise recent data describing a role for azacytidine-sensitive RNA methylation in lineage commitment and in the cellular response to stress. By summarising and interpreting evidence for azanucleoside involvement in a range of cellular processes, our review is intended to illustrate the need to consider multiple modes of action in the design and stratification of future combination therapies.

Comprehensive analysis of m6A methylome alterations after azacytidine plus venetoclax treatment for acute myeloid leukemia by nanopore sequencing

“…First of all, there was a significant reduction in the abundance of m 6 A sites and m 6 A levels throughout the entire genome of AML patients following AZA/VEN treatment. AZA plays the predominate demethylating role, whereas VEN is primarily a B-cell lymphoma 2 (BCL-2) inhibitor that selectively inhibits the survival signaling pathway of leukemia cells [7] , [50] . To examine the impact of demethylation drug on the RNA methylation patterns in leukemic cells, AZA was selected to treat HL-60 alone at IC 50 concentrations.…”

“…VEN plus AZA (VEN/AZA) is an emerging therapy that can regulate epigenetics, which refers to stably heritable phenotypes resulting from changes in a chromosome without alterations in the DNA/RNA sequence (e.g., DNA 5-methylcytosine and RNA N6-methyladenosine) [6] , and has been widely used in the clinical treatment of AML. AZA plays a predominant role in demethylation, acting on DNA, RNA, and protein metabolism [7] . However, the effect of AZA treatment on RNA methylation levels is undetermined in AML.…”

Global 5-methylcytosine-RNA disruption reduces the vectorial competence to DENV2 of heatwave-exposedAedes aegyptimosquitoes

“…5mC is also recognized for its involvement in various metabolic processes, including protein synthesis, energy metabolism, and lipid metabolism (15)(16)(17)(46)(47)(48)(49)51). The 5mC at C38 in tRNA-Asp is known to be related to three critical mechanisms: (1) an increased rate of tRNA/amino acid loading by aspatyl tRNA synthetase, (2) enhanced tRNA stability, and (3) improved fidelity in anticodon/codon interaction, minimizing mistranslation of glutamate to aspartate codons (as reviewed in: (28). Thus, the role of methylation in the context of inhibition may compromise protein synthesis.…”

“…Nucleoside analogues, such as azacytidine inhibit DNMT2 activity. Substitution of C5 in cytosine for N5 in azacytidine inhibits C5 methylation and disrupts beta-elimination, leaving the enzyme covalently bound to the nucleic acid and subsequently degraded (Reviewed in: (26)(27)(28). 5mC is removed by demethylases and recognized by methyl group-binding proteins, which exert regulatory functions after binding (24).…”

Therapeutic Applications of Azanucleoside Analogs as DNA Demethylating Agents

“…The focus of this review is mainly on the therapeutic applications of azanucleosides as single agents or in combination therapy and the rationale for these combinations. The multiple mechanisms of antitumor activity of these drugs and their effect on cellular differentiation, cell cycle arrest, and apoptosis are discussed in detail in other reviews [ 2 , 3 , 4 ].…”