Drug-tolerant persister cells in acute myeloid leukemia: pressing challenge and promising new strategies for treatment

Abstract

Acute myeloid leukemia (AML) exhibits a pronounced ability to develop drug resistance and undergo disease relapse. Recent research has noticed that resistance to treatments could substantially be attributed to drug-tolerant persister (DTP) cells, which are capable of surviving under therapeutic pressures. These are transient, reversibly dormant cells with the capability to act as a reservoir for disease relapse. DTP cells utilize diverse adaptive strategies to optimize the ecological niche, undergo metabolic reprogramming, and interact with microenvironment. The persister state of AML is established through transient cellular reprogramming, thus allowing cells to survive the initial phase of drug therapy and develop drug resistance. Our review explores the identification and phenotypic characteristics of AML DTP cells, as well as their clinical relevance. We summarize the mechanisms underlying the persistence of AML DTP cells and the molecular attributes that define the DTP state. We further address the current challenges and future prospects of DTP-targeting approaches. Understanding these features may provide critical insights into novel therapeutic strategies aimed at targeting AML DTP cells, especially in the new era of immunotherapy against AML.

Keywords: acute myeloid leukemia; chemotherapy resistance; drug tolerant persister; metabolic remodelling; minimal residual disease; relapse.

FIGURE 1

Epigenetic and transcriptional regulation.

FIGURE 2

Metabolic remodeling resulting in DTP cells depending on mitochondrial respiration for energy production and having increased antioxidant capacity. ATP, Adenosine triphosphate; FAO, fatty acid β-oxidation; GSH-Px, glutathione peroxidases; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species.

FIGURE 3

Up-regulation of genes associated with inflammatory pathways in DTP cells. GR, glucocorticoid receptors.

FIGURE 4

Leukemic-microenvironment interaction, particularly involving leukemia-associated fibroblasts within the reactive stroma. LAFs, leukemia-associated fibroblasts.