How Azanucleosides Affect Myeloid Cell Fate.
Anna SteinUwe PlatzbeckerMichael CrossPublished in: Cells (2022)
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.
Keyphrases
- dna methylation
- cell fate
- acute myeloid leukemia
- genome wide
- stem cells
- gene expression
- dendritic cells
- bone marrow
- transcription factor
- immune response
- mesenchymal stem cells
- single cell
- electronic health record
- high grade
- copy number
- single molecule
- circulating tumor
- current status
- deep learning
- machine learning
- artificial intelligence
- smoking cessation