Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells

Jones, Courtney L.; Stevens, Brett M.; D’Alessandro, Angelo; Reisz, Julie A.; Culp‐Hill, Rachel; Nemkov, Travis; Pei, Shanshan; Khan, Nabilah; Adane, Biniam; Ye, Haobin; Krug, Anna; Reinhold, Dominik; Smith, Clayton A.; DeGregori, James; Pollyea, Daniel A.; Jordan, Craig T.

doi:10.1016/j.ccell.2019.01.013

Cited by 150 publications

(257 citation statements)

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“…More recently, Stevens et al () added to these findings, showing that upregulation of the interleukin‐3 (IL‐3) receptor alpha chain, CD123, on MDS stem cells designates changes in cellular physiology. Specifically, CD123 + MDS stem cells had elevated levels of protein synthesis and significant changes in cellular energy metabolism that render them susceptible to pharmacological intervention, similar to their recent findings in AML (Jones et al , ; Pollyea et al , ). Targeting protein synthesis and energy metabolism was effective at eliminating MDS stem cells both in vitro and in vivo , yet again revealing similarities between LSCs from multiple different myeloid malignancies.…”

Section: Cancer Cell Metabolism In Myeloid Lscssupporting

confidence: 75%

“…ROS‐low AML LSCs were shown to be metabolically dormant, have increased levels of glutathioine, and demonstrate a dependency on oxidative respiration rather than glycolysis for energy production, in stark contrast to their normal counterparts or the bulk tumour population (Lagadinou et al , ). More recently, the dependence of AML LSCs on oxidative phosphorylation was formally established by assessing the effects of glucose depletion on the LSC population versus the bulk leukaemia population (Jones et al , ). In contrast to the previous theory of a dependence on glycolysis, AML LSCs did not respond to glucose depletion, whereas the bulk of AML cells were highly dependent on glucose.…”

Section: Cancer Cell Metabolism In Myeloid Lscsmentioning

confidence: 99%

“…In contrast to LSCs from patients with newly diagnosed AML, LSCs from relapsed AML patients were not dependent on amino acid metabolism for their survival, but were rather dependent on increased fatty acid metabolism, suggesting another metabolic vulnerability in patients after relapse (Jones et al , ). In fact, evidence suggests there may be fundamental differences between pre‐treatment LSCs and cells present after therapy in AML patients.…”

Section: Cancer Cell Metabolism In Myeloid Lscsmentioning

confidence: 99%

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Energy metabolism and drug response in myeloid leukaemic stem cells

et al. 2019

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Summary Despite significant advances in the treatment of myeloid malignancies, many patients become resistant to therapy and ultimately succumb to their disease. Accumulating evidence over the past several years has suggested that the inadequacy of many leukaemia therapies results from their failure to target the leukaemic stem cell (LSC). For this reason, the LSC population currently represents the most critical target in the treatment of myeloid malignancies. However, while LSCs are ideal targets in the treatment of these diseases, they are also the most difficult population to target. This is due to both their heterogeneity within the LSC population, and also their phenotypic similarities with normal haematopoietic stem cells. This review will highlight the current landscape surrounding LSC biology in myeloid malignancies, with a focus on altered energy metabolism, and how that knowledge is being translated into clinical advances for the treatment of chronic and acute myeloid leukaemia and myelodysplastic syndromes.

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Section: Cancer Cell Metabolism In Myeloid Lscssupporting

confidence: 75%

Section: Cancer Cell Metabolism In Myeloid Lscsmentioning

confidence: 99%

Section: Cancer Cell Metabolism In Myeloid Lscsmentioning

confidence: 99%

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Energy metabolism and drug response in myeloid leukaemic stem cells

et al. 2019

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“…Furthermore, combination of venetoclax with azacitidine resulted in deep and durable remissions with superior outcomes in elderly AML patients (Pollyea et al, 2018). This effect was due to the suppression of oxidative phosphorylation, which has led to selective targeting of LSCs (Jones et al, 2018). Reliance on oxidative phosphorylation has also been reported in melanoma and pancreatic CSCs (Pollyea and Jordan, 2017).…”

Section: Inhibition Of Signaling Pathways Used By Cscsmentioning

confidence: 99%

Targeting Cancer Stemness in the Clinic: From Hype to Hope

et al. 2019

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Tumors are composed of non-homogeneous cell populations exhibiting varying degrees of genetic and functional heterogeneity. Cancer stem cells (CSCs) are capable of sustaining tumors by manipulating genetic and non-genetic factors to metastasize, resist treatment, and maintain the tumor microenvironment. Understanding the key traits and mechanisms of CSC survival provides opportunities to improve patient outcomes via improved prognostic models and therapeutics. Here, we review the clinical significance of CSCs and results of potential CSC-targeting therapies in various cancers. We discuss barriers to translating cues from pre-clinical models into clinical applications and propose new strategies for rational design of future anti-CSC trials.

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“…Recently, Jones et al demonstrated enhanced amino acid uptake and catabolism in LSCs, and that survival of these cells isolated de novo from AML patients were dependent on amino acid metabolism for oxidative phosphorylation (46). On the other hand, LSCs obtained from relapsed AML patients have been shown to acquire a compensatory ability to overcome the loss of amino acid metabolism by increasing FAO (46), suggesting that the eradication of chemoresistant LSCs could be achieved by targeting LSC metabolic vulnerabilities such as FAO dependency.…”

Section: Fao In Lscsmentioning

confidence: 99%

Fatty Acid Metabolism, Bone Marrow Adipocytes, and AML

2020

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Acute myeloid leukemia (AML) cells modulate their metabolic state continuously as a result of bone marrow (BM) microenvironment stimuli and/or nutrient availability. Adipocytes are prevalent in the BM stroma and increase in number with age. AML in elderly patients induces remodeling and lipolysis of BM adipocytes, which may promote AML cell survival through metabolic activation of fatty acid oxidation (FAO). FAO reactions generate acetyl-CoA from fatty acids under aerobic conditions and, under certain conditions, it can cause uncoupling of mitochondrial oxidative phosphorylation. Recent experimental evidence indicates that FAO is associated with quiescence and drug-resistance in leukemia stem cells. In this review, we highlight recent progress in our understanding of fatty acid metabolism in AML cells in the adipocyte-rich BM microenvironment, and discuss the therapeutic potential of combinatorial regimens with various FAO inhibitors, which target metabolic vulnerabilities of BM-resident, chemoresistant leukemia cells.

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Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells

Cited by 150 publications

References 0 publications

Energy metabolism and drug response in myeloid leukaemic stem cells

Energy metabolism and drug response in myeloid leukaemic stem cells

Targeting Cancer Stemness in the Clinic: From Hype to Hope

Fatty Acid Metabolism, Bone Marrow Adipocytes, and AML

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