Dietary methionine starvation impairs acute myeloid leukemia progression

Abstract

Targeting altered tumor cell metabolism might provide an attractive opportunity for patients with acute myeloid leukemia (AML). An amino acid dropout screen on primary leukemic stem cells and progenitor populations revealed a number of amino acid dependencies, of which methionine was one of the strongest. By using various metabolite rescue experiments, NMR-based metabolite quantifications and 13C-tracing, polysomal profiling, and ChIP-seq, we identified that methionine is used predominantly for protein translation and to provide methyl groups to histones via S-adenosylmethionine for epigenetic marking. H3K36me3 was consistently the most heavily impacted mark following loss of methionine. Methionine depletion also reduced total RNA levels, enhanced apoptosis and induced a cell cycle block. ROS levels were not increased following methionine depletion and replacement of methionine with glutathione or N-acetylcysteine could not rescue phenotypes, excluding a role for methionine in controlling redox balance control in AML. Although considered to be an essential amino acid, methionine can be recycled from homocysteine. We uncovered that this is primarily performed by the enzyme methionine synthase and only when methionine availability becomes limiting. In vivo, dietary methionine starvation was not only tolerated by mice, but also significantly delayed both cell line and patient-derived AML progression. Finally, we show that inhibition of the H3K36-specific methyltransferase SETD2 phenocopies much of the cytotoxic effects of methionine depletion, providing a more targeted therapeutic approach. In conclusion, we show that methionine depletion is a vulnerability in AML that can be exploited therapeutically, and we provide mechanistic insight into how cells metabolize and recycle methionine.

Increased response to immune checkpoint inhibitors with dietary methionine restriction

“…There was a significant decrease in hemoglobin in the methionine-restricted group in both females and males, with a small but significant decrease in red blood cells in females. To our knowledge, hemoglobin values have not been previously reported in methionine restriction but are in line with data reported for complete methionine starvation in acute myeloid leukemia (28). We then performed immunohistochemistry on the tumor tissue.…”

Feasible diet and circadian interventions reduce in vivo progression of FLT3‐ITD‐positive acute myeloid leukemia

“…Many studies such as this have identified high‐fat diet to worsen leukemia progression, 3 but none have implemented a low‐fat diet as a possible intervention to improve treatment. One study identified AML cells to be high in amino acids such as methionine, cysteine, and lysine, and showed that depleted methionine from the diet in vivo slowed leukemic progression 26 . However amino acid depletion diets are difficult to implement in clinical settings, as this requires a very specific diet formulation and strict adherence.…”

“…One study identified AML cells to be high in amino acids such as methionine, cysteine, and lysine, and showed that depleted methionine from the diet in vivo slowed leukemic progression. 26 However amino acid depletion diets are difficult to implement in clinical settings, as this requires a very specific diet formulation and strict adherence.…”

Specific regulation of epigenome landscape by metabolic enzymes and metabolites

“…SAM is synthesised by methionine adenosyltransferase (MAT) from methionine in the one‐carbon metabolism pathway. Methionine depletion reduces SET‐domain containing 2 (SETD2)‐catalysed H3K36me3, which is accompanied by decreased transcription, enhanced apoptosis, and cell cycle arrest (Cunningham et al ., 2022). Methionine deficiency also leads to reduced SAM levels and specific declines in H3K4 methylation in yeast, Caenorhabditis elegans and human cells (Sadhu et al ., 2013; Ding et al ., 2015).…”