The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia

Alan Cunningham, Lieve Oudejans, Marjan Geugien, Diego A Pereira-Martins, Albertus TJ Wierenga, Ayşegül Erdem, Dominique Sternadt, Gerwin A Huls, Jan Jacob Schuringa*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

3 Citaten (Scopus)
34 Downloads (Pure)

Samenvatting

Cysteine is a non-essential amino acid required for protein synthesis, the generation of the anti-oxidant glutathione and for synthesizing the non-proteinogenic amino acid taurine. Here, we highlight the broad sensitivity of leukemic stem and progenitor cells to cysteine depletion. By CRISPR/Cas9-mediated knockout of cystathionine-γ-Lysase (CTH), the cystathionine to cysteine converting enzyme, and by metabolite supplementation studies upstream of cysteine, we functionally prove that cysteine is not synthesized from methionine in acute myeloid leukemia (AML) cells. Therefore, while perhaps nutritionally non-essential, cysteine must be imported for survival of these specific cell types. Depletion of cyst(e)ine increased reactive oxygen species (ROS) levels and cell death was induced predominantly as a consequence of glutathione deprivation. NADPH oxidase (NOX) inhibition strongly rescued viability following cysteine depletion, highlighting this as an important source of ROS in AML. ROS-induced cell death was mediated via ferroptosis, and inhibition of GPX4, which functions to reduce lipid peroxides, was also highly toxic and we therefore propose that GPX4 is likely key in mediating the antioxidant activity of glutathione. In line, inhibition of the ROS scavenger thioredoxin reductase with Auranofin also impaired cell viability, whereby we find that in particular OXPHOS-driven AML subtypes are highly dependent on thioredoxin-mediated protection against ferroptosis. While inhibition of the cystine importer xCT with Sulfasalazine was ineffective as a monotherapy, its combination with L-buthionine-sulfoximine (BSO) further improved AML ferroptosis induction. We propose the combination of either Sulfasalazine or anti-oxidant machinery inhibitors along with ROS inducers such as BSO or chemotherapy for further pre-clinical testing.

Originele taal-2English
Pagina's (van-tot)56–69
Aantal pagina's14
TijdschriftBlood Advances
Volume8
Nummer van het tijdschrift1
Vroegere onlinedatum31-okt.-2023
DOI's
StatusPublished - 9-jan.-2024

Vingerafdruk

Duik in de onderzoeksthema's van 'The nonessential amino acid cysteine is required to prevent ferroptosis in acute myeloid leukemia'. Samen vormen ze een unieke vingerafdruk.

Citeer dit