Epigenetic therapy combinations in acute myeloid leukemia: what are the options?

Abstract

Epigenetics refers to the regulation of gene expression mainly by changes in DNA methylation and modifications of histone proteins without altering the actual DNA sequence. While epigenetic modifications are essential for normal cell differentiation, several driver mutations in leukemic pathogenesis have been identified in genes that affect epigenetic processes, such as DNA methylation and histone acetylation. Several therapeutic options to target epigenetic alterations in acute myeloid leukemia (AML) have been successfully tested in preclinical studies and various drugs have already been approved for use in clinical practice. Among these already approved therapeutics are hypomethylating agents (azacitidine and decitabine) and isocitrate dehydrogenase inhibitors (ivosidenib, enasidenib). Other agents such as bromodomain-containing epigenetic reader proteins and histone methylation (e.g. DOT1L) inhibitors are currently in advanced clinical testing. As several epigenetic therapies have only limited efficacy when used as single agents, combination therapies that target AML pathogenesis at different levels and exploit synergistic mechanisms are also in clinical trials. Combinations of either epigenetic therapies with conventional chemotherapy, different forms of epigenetic therapies, or epigenetic therapies with immunotherapy are showing promising early results. In this review we summarize the underlying pathophysiology and rationale for epigenetically-based combination therapies, review current preclinical and clinical data and discuss the future directions of epigenetic therapy combinations in AML.

Keywords: AML; DNA methylation; acute myelogenous leukemia; acute myeloid leukemia; combination therapy; epigenetic therapy; histone deacetylase inhibitors; histones; hypomethylating agent.

Figure 1.

Overview of epigenetic mechanisms and selected therapeutic interventions. Epigenetics refer to the modification of the chromatin structure without altering the base pair sequence of the DNA itself which is an essential process for regulating gene transcription and cell differentiation in both physiological conditions and malignant cell transformation. Epigenetic modifications can occur in the form of DNA methylation/hydroxymethylation, histone protein modifications (acetylation, methylation) and changes to higher-order chromatin structures. Methylation of CpG islands in the DNA generally suppress gene transcription and is mediated by DNA methyltransferases (DNMT). Alterations in DNA methylation have been linked to AML development and treatment with hypomethylating agents (e.g. azacitidine, decitabine) that inhibit DNMT has been successfully used in AML patients. On the other hand, DNA hydroxymethylation enhances gene transcription and is mediated by α-ketoglutarate-dependent enzymes such as TET2. IDH1/2 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate instead of α-ketoglutarate which blocks DNA hydroxymethylation. The action of mutated IDH1/2 can be blocked by enasidenib and ivosidenib which restores function of enzymes orchestrating DNA hydroxymethylation. The DNA double-strand is stored in cells as a complex with histone proteins. Acetylation of histone proteins reduces the access of transcription factors to the DNA strand and thereby prevents gene transcription. Histone acetylation status is regulated by balancing the activity of histone deacetylases and histone acetylases which can be therapeutically targeted by bromodomain inhibitors and histone deacetylase (HDAC) inhibitors. Methylation and demethylation of histone proteins can occur at different sites of the histone molecule and is mediated by histone methyltransferases and histone demethylases. DOT1L is a histone H3K79 methyltransferase while EZH1/2 methylates histone H3K27 and both have both implicated in leukemogenesis and can be targeted by specific inhibitors. Histone demethylation can be blocked by LSD1 inhibitors.