Acute myeloid leukemia (AML) cells are dependent on several amino acids, including methionine, and dietary depletion of methionine inhibited AML progression in mice, according to the results of study published in the journal Blood.
Methionine, and to a lesser extent, cysteine, arginine, glutamine, and lysine, were found to be critical to primary leukemic stem cells and progenitor cells. Given the strong dependence of AML cells to methionine, the study further evaluated its role in AML cell lines and mouse models.
In vitro, methionine was used for protein translation and for histones used for epigenetic marking. Methionine depletion in AML cells altered the metabolic state, as indicated by decreased glucose consumption and lactate secretion. The cell cycle was also affected by methionine depletion, with arrest ag the G0-G1 checkpoint and increased apoptosis.
Methionine depletion in vitro decreased histone methylation, which affected epigenetic markers, particularly H3K27me3. The authors also observed a decrease in total RNA and translation to proteins.
Knockout mice of proteins needed for homocysteine recycling in AML cells were developed to assess the effect of dietary methionine depletion. In these mice, depletion of dietary methionine prolonged progression of cell line- and patient-derived AML and was well tolerated.
The depletion of dietary methionine could be mimicked using STED2 inhibitors, which target and reduce H3K36me3. The results could be mitigated by supplementation with homocysteine. The authors concluded that “our data highlight how amino acid metabolism can be manipulated to target genetically diverse AML cells.”
Cunningham A, Erdem A, Alshamleh I, et al. Dietary methionine starvation impairs acute myeloid leukemia progression. Blood. 2022;140:2037-2052. doi: 10.1182/blood.2022017575