Susceptibility of acute myeloid leukemia cells to ferroptosis and evasion strategies

Abstract

Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy with a 5-year survival rate of less than 30%. Continuous updating of diagnostic and therapeutic strategies has not been effective in improving the clinical benefit of AML. AML cells are prone to iron metabolism imbalance due to their unique pathological characteristics, and ferroptosis is a novel cell death mode that is dominated by three cellular biological processes: iron metabolism, oxidative stress and lipid metabolism. An in-depth exploration of the unique ferroptosis mechanism in AML can provide new insights for the diagnosis and treatment of this disease. This study summarizes recent studies on ferroptosis in AML cells and suggests that the metabolic characteristics, gene mutation patterns, and dependence on mitochondria of AML cells greatly increase their susceptibility to ferroptosis. In addition, this study suggests that AML cells can establish a variety of strategies to evade ferroptosis to maintain their survival during the process of occurrence and development, and summarizes the related drugs targeting ferroptosis pathway in AML treatment, which provides development directions for the subsequent mechanism research and clinical treatment of AML.

Antioxidant Systems as Modulators of Ferroptosis: Focus on Transcription Factors

“…Accordingly, a large body of work has recently highlighted the role of ferroptosis in acute myeloid leukemia (AML). Metabolic pathways typically altered in AML and related to ROS/RNS production include enzymes like nitric oxide synthase (NOS), CYP, NAD(P)H oxidase (NOX), and COX (reviewed in [ 70 ]). The high frequency of ROS/RNS overproduction in leukemia clearly implies that they are related to the etiology of this disease [ 71 ].…”

“…Low levels of ROS, on the other hand, protect AML cells from apoptosis and increase treatment resistance, cell migration, growth, and proliferation [ 61 , 74 ]. AML cells are particularly sensitive to iron overload, and although there is strong evidence that transferrin is highly expressed in these cells with increased binding activity, the exact effect of transferrin on AML cells is unclear [ 70 ]. Therefore, ferroptosis is emerged as a therapeutic target in leukemia.…”

Latest Insights and Progress in the Clinical Management of Elderly Patients with Acute Myeloid Leukemia: From Genetic Advancements to Targeted Treatments

“…Furthermore, an emerging understanding of the role of tumoral angiogenesis and the impact of endothelial cell subsets in shaping BM niches have been reported [39]. Moreover, it is relevant to note that AML cells can use different strategies to avoid ferroptosis cell death, controlled by three main cellular processes: iron metabolism, oxidative stress, and lipid metabolism [40]. Additionally, transcription factors, such as HOXA9, are overexpressed in approximately 70% of AML cases with poor prognosis, increased chemoresistance, and higher relapse rates [41].…”

“…This NES interacts with the nucleus cell exporter Exportin-1 (XPO1), causing accumulation of the NPM1 mutant in the cytoplasm [60,61]. The overexpression of the HOX gene [40], similar to KMT2A rearranged AML, guides the NPM-1 mutated AML development. Notably, overlapping features between t-NPM1 and de novo NPM1 AMLs suggest they can represent a single disease entity [67].…”

Emerging role of glutathione peroxidase 4 in myeloid cell lineage development and acute myeloid leukemia

“…Importantly, the same authors also reported that AML cells were unable to synthetize cysteine from methionine providing an opportunity to exploit this vulnerability for AML treatment. Of note, AML patients with high SLC7A11 mRNA expression exhibited a drastically lower overall survival than patients with low SLC7A11 expression [ 42 , 43 ].…”