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Review
. 2020 Mar 20;133(6):699-715.
doi: 10.1097/CM9.0000000000000685.

Epigenetic therapies in acute myeloid leukemia: the role of hypomethylating agents, histone deacetylase inhibitors and the combination of hypomethylating agents with histone deacetylase inhibitors

Qing-Yu Xu  1   2 , Li Yu  1
Affiliations
Review

Epigenetic therapies in acute myeloid leukemia: the role of hypomethylating agents, histone deacetylase inhibitors and the combination of hypomethylating agents with histone deacetylase inhibitors

Qing-Yu Xu et al. Chin Med J (Engl). .

Abstract

Epigenetic regulation includes changes of DNA methylation and modifications of histone proteins and is essential for normal physiologic functions, especially for controlling gene expression. Epigenetic dysregulation plays a key role in disease pathogenesis and progression of some malignancies, including acute myeloid leukemia (AML). Epigenetic therapies, including hypomethylating agents (HMAs) and histone deacetylase (HDAC) inhibitors, were developed to reprogram the epigenetic abnormalities in AML. However, the molecular mechanisms and therapeutic effects of the two agents alone or their combination remain unknown. An overview of these epigenetic therapies is given here. A literature search was conducted through PubMed database, looking for important biological or clinical studies related to the epigenetic regimens in the treatment of AML until October 15th, 2019. Various types of articles, including original research and reviews, were assessed, identified, and eventually summarized as a collection of data pertaining the mechanisms and clinical effects of HMAs and HDAC inhibitors in AML patients. We provided here an overview of the current understanding of the mechanisms and clinical therapeutic effects involved in the treatment with HMAs and HDAC inhibitors alone, the combination of epigenetic therapies with intensive chemotherapy, and the combination of both types of epigenetic therapies. Relevant clinical trials were also discussed. Generally speaking, the large number of studies and their varied outcomes demonstrate that effects of epigenetic therapies are heterogeneous, and that HMAs combination regimens probably contribute to significant response rates. However, more research is needed to explore therapeutic effects of HDAC inhibitors and various combinations of HMAs and HDAC inhibitors.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Overview of therapeutic mechanisms for epigenetic therapies and their combinations. Decitabine triphosphate from DAC and 5-AZA competitively replaces cytosine in the CpG islands occurring in clusters of promoter regions, and sequentially inhibits methylation level of the promoter, based on a covalent bond with the DNMT enzymes. This procedure resulted in eventual degradation of these enzymes, followed by reduced DNA methylation level and methylation-induced gene silencing. Additionally, the combination of HMAs with cytarabine or anthracycline has a synergistic anti-leukemic influence, and HMAs can also work as chemosensitizers, restore expression level of tumor suppressor genes and eventually improve the susceptibility to chemotherapies. HDAC inhibitors mainly inhibit excessive histone deacetylation, with the functions of: (i) inhibiting the G1 phase of the cell cycle, (ii) promoting cell apoptosis and autophagy, and (iii) leading to DNA defects that cause cell death during mitosis. HDAC inhibitors have shown synergistic effect when combined with intensive chemotherapies. And it is assumed that HDAC inhibitors help formulating a more open chromatin structure that probably allows for more extensive access of topoisomerase inhibitors to the DNA structure and thereby causing higher therapeutic effects of chemotherapies. In addition, a combination of HMAs with HDAC inhibitors also has a synergistic effect, resulting in significantly higher transcripts than either treatment alone, inducing cell apoptosis, inhibiting cell proliferation, promoting histone acetylation, further inhibiting of the DNMT enzymes, and eventually showing a clear synergistic anti-leukemic effect. 5-AZA: 5-Azacytidine; DAC: Decitabine; HMAs: Hypomethylating agents; HDAC: Histone deacetylase.
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