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Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II

Courtney L. Jones, Brett M. Stevens, Angelo D'Alessandro, Rachel Culp-Hill, Julie A. Reisz, Shanshan Pei, Annika Gustafson, Nabilah Khan, James DeGregori, Daniel A. Pollyea and Craig T. Jordan

Key Points

  • Leukemia stem cells rely on cysteine for survival.

  • Cysteine metabolism is required for electron transport chain complex II activity in LSCs.

Abstract

We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from acute myeloid leukemia (AML) patients. More recently, we demonstrated that LSCs in de novo AML patients rely on amino acid metabolism to drive oxidative phosphorylation. Notably, while overall levels of amino acids contribute to LSC energy metabolism, our current findings suggest that cysteine may be of particular importance for LSC survival. We demonstrate that exogenous cysteine is metabolized exclusively to glutathione. Upon cysteine depletion, glutathione synthesis is impaired, leading to reduced glutathionylation of succinate dehydrogenase A (SDHA), a key component of electron transport chain complex (ETC) II. Loss of SDHA glutathionylation impairs ETC II activity, thereby inhibiting oxidative phosphorylation, reducing production of ATP and leading to LSC death. Given the role of cysteine in driving LSC energy production we tested cysteine depletion as a potential therapeutic strategy. Using a novel cysteine-degrading enzyme we demonstrate selective eradication of LSCs, with no detectable effect on normal hematopoietic stem/progenitor cells. Together, these findings indicate that LSCs are aberrantly reliant on cysteine to sustain energy metabolism and that targeting this axis may represent a useful therapeutic strategy.

  • Submitted January 22, 2019.
  • Revision received May 14, 2019.
  • Accepted May 8, 2019.