Intersection of Epigenetic and Metabolic Regulation of Histone Modifications in Acute Myeloid Leukemia.

Abhinav Dhall,Fangxue Yan,Barry M Zee,M Andres Blanco

doi:10.3389/fonc.2019.00432

Abhinav Dhall, Fangxue Yan + Show 2 more

Open Access

https://doi.org/10.3389/fonc.2019.00432

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Abstract

Acute myeloid leukemia (AML) is one of the most lethal blood cancers, accounting for close to a quarter of a million annual deaths worldwide. Even though genetically heterogeneous, all AMLs are characterized by two interrelated features—blocked differentiation and high proliferative capacity. Despite significant progress in our understanding of the molecular and genetic basis of AML, the treatment of AMLs with chemotherapeutic regimens has remained largely unchanged in the past 30 years. In this review, we will consider the role of two cellular processes, metabolism and epigenetics, in the development and progression of AML and highlight the studies that suggest an interconnection of therapeutic importance between the two. Large-scale whole-exome sequencing of AML patients has revealed the presence of mutations, translocations or duplications in several epigenetic effectors such as DNMT3, MLL, ASXL1, and TET2, often times co-occuring with mutations in metabolic enzymes such as IDH1 and IDH2. These mutations often result in impaired enzymatic activity which leads to an altered epigenetic landscape through dysregulation of chromatin modifications such as DNA methylation, histone acetylation and methylation. We will discuss the role of enzymes that are responsible for establishing these modifications, namely histone acetyl transferases (HAT), histone methyl transferases (HMT), demethylases (KDMs), and deacetylases (HDAC), and also highlight the merits and demerits of using inhibitors that target these enzymes. Furthermore, we will tie in the metabolic regulation of co-factors such as acetyl-CoA, SAM, and α-ketoglutarate that are utilized by these enzymes and examine the role of metabolic inhibitors as a treatment option for AML. In doing so, we hope to stimulate interest in this topic and help generate a rationale for the consideration of the combinatorial use of metabolic and epigenetic inhibitors for the treatment of AML.

Highlights

All cancers are a result of highly proliferative cells but accompanying blockade in differentiation is pronounced in certain leukemias such as Acute myeloid leukemia (AML)
We propose that programs such as these— perhaps in altered or misfunctional form—are directly relevant to AML biology, as differentiation blockade and cell fate dysregulation are hallmarks of this disease
Even though single drug therapies have so far been the major focus in the attempt to restore the balance of histone acetylation in secondary and refractory AML, the most promising therapeutic leads have come from the simultaneous inhibition of HDACs and the mTOR/Akt axis

Summary

Introduction

We propose that the mitochondria-chromatin connection can be exploited in cases beyond IDH1/2 mutant AMLs. We derive this view in part from models of normal myeloid cell differentiation programs. Numerous studies have demonstrated the interaction between metabolic dynamics and epigenome regulation in classical cell fate models such as macrophage activation and trained immunity [reviewed in [18]] Upon classical macrophage activation by LPS stimulation, a switch from oxidative phosphorylation to glycolysis occurs rapidly, producing a buildup of lactate—which has been shown to directly antagonize class II HDACs [19].

Results

Conclusion