A recent review published in Biomedicines covers the emerging field of epitranscriptomics and the prospects of precision medicines that target acute myeloid leukemia (AML)-associated genes, including 6-methyladenosine (m6A) modifiers, microRNAs, and suppressors of cytokine signaling.
Epitranscriptomics, also called RNA epigenetics, encompasses the study of RNA modifications that do not affect the RNA sequence but affect its functionality, including alternative splicing, nuclear export, transcript stability, and translation. RNA binding proteins called writer, reader, and eraser induce epi-RNA modifications, such as m6A, 5-methylcytidine (m5C), and 1-methyladenosine. The m6A modification is the most well-studied and has therapeutic implications.
The m6A-writer proteins Mettl3 and Mettl14 have been associated with specific subtypes of AML, wherein their aberrant expression promotes leukemogenesis by regulating pathways that include proto-oncogenes, such as MYB, MYC, Bcl2, pTEN, and PI3K-AKT.
Another writer, m6A-methylase, and the m6A-demethylases FTO and ALKBH5, which function as erasers, have been associated with acute promyelocytic leukemia and leukemia stem/initiating cells (LSCs/LICs) and their aberrant expression promotes leukemogenesis by regulating disease-associated proteins, including ASB2, RARA, LILRB4, CEBPA, TACC3, MYC, and P-21.
The reader protein YTHDF20 appears to promote leukemogenesis via mRNA decay mechanisms that suppress proteins involved in hematopoietic stem cell expansion (Tla1) and immune function (TNF-α). Taken together, these finding suggest that epitranscriptomic modifiers promote AML via different mechanisms that impact the regulation of numerous disease-associated pathways.
Given the relationship between RNA-modifying proteins and cancer-associated pathways, the development of novel therapeutic drugs that target m6A-modification mechanisms is now of considerable interest in the field of epigenetics. Therapeutic strategies include selective inhibition or targeted therapy/silencing of Mettl-3/14, FTO/ALKBH5, and reader proteins. The authors suggested that cotargeting of genes that act intracellularly along with m6A-modification machineries may improve immunotherapy against cancers that are resistant to immune checkpoint-based therapeutics.
Additional potential therapeutic mechanisms include microRNA-mediated silencing of transcripts that promote leukemogenesis. MicroRNAs (miR), including miR-150, miR-34a, and miR-29b, have been shown to have anti-leukemic effects via suppression of Wnt- and mTOR-signaling, MYC, and Sp1/FUT4-fucosylations.
The authors also highlighted the role of cytokine-inducible SH2-domain-containing protein (CISH or CIS), which has demonstrated anti-tumor and anti-leukemia activity via its ability to sensitize immune cells and regulate cytokine signaling. CISH knockdown has been shown to enhance the function of dendritic cells, T cells, and NK cells. Furthermore, CISH appears to interact with m6a writer- and reader-mediated mechanisms.
“Pharmaceutical approaches pertaining to RNA epigenetic modification machinery are expected to shed light on the field of cancer immunotherapy for AML and other forms of blood cancer,” the authors wrote.
Biopharmaceutical companies, including Accent Therapeutics (US), Gotham Therapeutics (US), and Storm Therapeutics (UK), are currently developing RNA-modifying drugs, and clinical trials evaluating these agents, such as selective inhibitors of the Mettl-3/14 in AML, are expected in 2021 and 2022.
Kumar S, Nagpal R, Kumar A, Ashraf MU, Bae YS. Immunotherapeutic potential of m6A-modifiers and microRNAs in controlling acute myeloid leukaemia. Biomedicines. 2021;9(6):690. doi:10.3390/biomedicines9060690