Abstract
Recent studies have uncovered an important role for RNA modifications in gene expression regulation, which led to the birth of the epitranscriptomics field. It is now acknowledged that RNA modifiers play a crucial role in the control of differentiation of stem and progenitor cells and that changes in their levels are a relevant feature of different types of cancer. To date, among more than 160 different RNA chemical modifications, the more relevant in cancer biology is the reversible and dynamic N6-methylation of adenosine, yielding N6-methyladenosine (m6A). m6A is the more abundant internal modification in mRNA, regulating the expression of the latter at different levels, from maturation to translation. Here, we will describe the emerging role of m6A modification in acute myeloid leukemia (AML), which, among first, has demonstrated how mis-regulation of the m6A modifying system can contribute to the development and progression of cancer. Moreover, we will discuss how AML is paving the way to the development of new therapeutic options based on the inhibition of m6A deposition.
Highlights
Chemical modifications in eukaryotic RNAs are known from decades
One of most studied RNA modifications with a well-define role in gene expression regulation is the N6-methyladenosine (m6A), which is present in all RNA species including mRNAs, lncRNAs, rRNAs, tRNAs, and snRNAs
We will focus on the dynamic m6A modification of mRNAs. m6A is the most abundant internal modification in mRNA where it can be embedded and erased by specific proteins [1,2,3,4,5]. m6A mark can recruit reader proteins, such as the YT521-B homology (YTH) domain family of proteins, or it can produce conformational changes within local RNA structures that may indirectly affect the interaction with RNA binding protein [6,7,8,9]
Summary
Chemical modifications in eukaryotic RNAs are known from decades. until recent years, their role in cancer development was largely unknown. In a first study performed on the MOLM-13 AML cell lines, which carries the FLT3 internal tandem duplication (FLT3-ITD) that in patients is associated with a more aggressive disease, knockdown of METTL3 resulted in a m6A dependent reduction of c-MYC, BCL2 and PTEN mRNA translation while the overexpression of METTL3 produced increased protein levels of all three proteins [37]. A second study performed again in MOLM-13 cells, showed that METTL3 is recruited on specific promoter transcription start sites (TSS) by the transcription factor CCAAT enhancer binding protein zeta (CEBPZ, known as DDIT3 and CHOP) [41] This has been indicated as a mechanism that produces co-transcriptional m6A modification on specific RNAs. Notably, CEBPZ gene was found recurrently mutated in different AML subtypes [46, 47], suggesting that this might result in altered recruitment of METTL3.
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