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

Blood - Tập 134 Số 4 - Trang 389-394 - 2019
Courtney L. Jones1, Brett M. Stevens1, Angelo D’Alessandro2, Rachel Culp‐Hill2, Julie A. Reisz2, Shanshan Pei1, Annika Gustafson1, Nabilah Khan1, James DeGregori2, Daniel A. Pollyea1, Craig T. Jordan1
1Division of Hematology and
2Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO

Tóm tắt

Abstract We have previously demonstrated that oxidative phosphorylation is required for the survival of human leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML). More recently, we demonstrated that LSCs in patients with de novo AML rely on amino acid metabolism to drive oxidative phosphorylation. Notably, although 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.

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Tài liệu tham khảo

Pollyea, 2018, Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia, Nat Med, 24, 1859, 10.1038/s41591-018-0233-1

Jones, 2018, Inhibition of amino acid metabolism selectively targets human leukemia stem cells [published correction appears in Cancer Cell. 2019;35(2):333-335], Cancer Cell, 34, 724, 10.1016/j.ccell.2018.10.005

Lagadinou, 2013, BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells, Cell Stem Cell, 12, 329, 10.1016/j.stem.2012.12.013

Nemkov, 2015, Three-minute method for amino acid analysis by UHPLC and high-resolution quadrupole orbitrap mass spectrometry, Amino Acids, 47, 2345, 10.1007/s00726-015-2019-9

Pei, 2018, AMPK/FIS1-mediated mitophagy is required for self-renewal of human AML stem cells, Cell Stem Cell, 23, 86, 10.1016/j.stem.2018.05.021

Cramer, 2017, Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth, Nat Med, 23, 120, 10.1038/nm.4232

Pei, 2016, Rational design of a parthenolide-based drug regimen that selectively eradicates acute myelogenous leukemia stem cells, J Biol Chem, 291, 25280, 10.1074/jbc.A116.750653

Pei, 2013, Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells, J Biol Chem, 288, 33542, 10.1074/jbc.M113.511170

Chen, 2007, Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation, J Biol Chem, 282, 32640, 10.1074/jbc.M702294200

Cole, 2015, Inhibition of the mitochondrial protease ClpP as a therapeutic strategy for human acute myeloid leukemia, Cancer Cell, 27, 864, 10.1016/j.ccell.2015.05.004

DiNardo, 2018, Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies, Am J Hematol, 93, 401, 10.1002/ajh.25000

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Blood

Tập 134 Số 4

389-394

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