Dietary methionine starvation impairs acute myeloid leukemia progression

Alan Cunningham, Ayşegül Erdem, Islam Alshamleh, Marjan Geugien, Maurien Pruis, Diego Antonio Pereira-Martins, Fiona A.J. van den Heuvel, Albertus T.J. Wierenga, Hilde ten Berge, Robin Dennebos, Vincent van den Boom, Shanna M. Hogeling, Isabel Weinhäuser, Ruth Knops, Pim de Blaauw, M. Rebecca Heiner-Fokkema, Carolien Woolthuis, Ulrich L. Günther, Eduardo M. Rego, Joost H.A. MartensJoop H. Jansen, Harald Schwalbe, Gerwin Huls, Jan Jacob Schuringa*

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

19 Citaten (Scopus)
259 Downloads (Pure)

Samenvatting

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, nuclear magnetic resonance−based metabolite quantifications and 13C-tracing, polysomal profiling, and chromatin immunoprecipitation sequencing, 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. Reactive oxygen species 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.

Originele taal-2English
Pagina's (van-tot)2037–2052
Aantal pagina's16
TijdschriftBlood
Volume140
Nummer van het tijdschrift19
DOI's
StatusPublished - 10-nov.-2022

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