Crosstalk between DNA methylation and hypoxia in acute myeloid leukaemia

Abstract

Background: Acute myeloid leukaemia (AML) is a deadly disease characterised by the uncontrolled proliferation of immature myeloid cells within the bone marrow. Altered regulation of DNA methylation is an important epigenetic driver of AML, where the hypoxic bone marrow microenvironment can help facilitate leukaemogenesis. Thus, interactions between epigenetic regulation and hypoxia signalling will have important implications for AML development and treatment.

Main body: This review summarises the importance of DNA methylation and the hypoxic bone marrow microenvironment in the development, progression, and treatment of AML. Here, we focus on the role hypoxia plays on signalling and the subsequent regulation of DNA methylation. Hypoxia is likely to influence DNA methylation through altered metabolic pathways, transcriptional control of epigenetic regulators, and direct effects on the enzymatic activity of epigenetic modifiers. DNA methylation may also prevent activation of hypoxia-responsive genes, demonstrating bidirectional crosstalk between epigenetic regulation and the hypoxic microenvironment. Finally, we consider the clinical implications of these interactions, suggesting that reduced cell cycling within the hypoxic bone marrow may decrease the efficacy of hypomethylating agents.

Conclusion: Hypoxia is likely to influence AML progression through complex interactions with DNA methylation, where the therapeutic efficacy of hypomethylating agents may be limited within the hypoxic bone marrow. To achieve optimal outcomes for AML patients, future studies should therefore consider co-treatments that can promote cycling of AML cells within the bone marrow or encourage their dissociation from the bone marrow.

Keywords: Acute myeloid leukaemia; DNA methylation; Epigenetics; Hypoxia; Reactive oxygen species; Treatment outcomes.

Fig. 1

Common mutations in epigenetic regulators and their influence on DNA methylation in AML. In wild-type cells (black; top, left), the equilibrium between methylated (5mC) and unmodified (C) cytosines is governed by balanced DNMT3A and TET2 activity. IDH1/2 activity produces α-KG (orange), which is required for TET function. Loss of function DNMT3A mutations (green; bottom, left) lead to impaired DNMT3A activity and hypomethylation (purple). Conversely, loss of function TET2 (pink; top, right) or IDH1/2 (blue; bottom right) mutations result in hypermethylation (red). Mutations in IDH1/2 lead to the production of the oncometabolite 2-HG, which acts as a competitive inhibitor for TET2, resulting in decreased TET2 activity and hypermethylation (blue; bottom, right)

Fig. 2

Complex interactions between hypoxia and DNA methylation. Hypoxia may influence DNA methylation via direct effects on TET activity, altered transcription, or metabolic reprogramming. DNA methylation may also influence hypoxia responses. A Oxygen is an essential co-factor for TET enzymes, and hypoxia reduces TET-mediated DNA hydroxymethylation in some cancers. B In certain cell types, hypoxia-inducible factors (HIFα, HIFβ) bind to hypoxia-responsive elements (HREs) in TET and DNMT promoters to induce their expression. C In hypoxia, cancer cells can induce a metabolic switch from oxidative phosphorylation to glutamine metabolism. In IDH wild-type cells, upregulated glutamine metabolism has been associated with production of 2-HG which can inhibit TET enzymes. D DNA methylation can prevent the binding of HIF complexes to HREs, altering transcriptional responses induced by hypoxia