Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes

Matre, Polina; Vélez, Juliana; Jácamo, Rodrigo; Qi, Yuan; Su, Xiaoping; Cai, Tianyu; Chan, Steven M.; Lodi, Alessia; Sweeney, Shannon R.; Ma, Helen; Davis, R. Eric; Baran, Natalia; Haferlach, Torsten; Su, Xiaohua; Flores, Elsa R.; Gonzalez, Doriann; Konoplev, Sergej; Samudio, Ismael; DiNardo, Courtney D.; Majeti, Ravindra; Schimmer, Aaron D.; Li, Weiqun; Wang, Taotao; Tiziani, Stefano; Konopleva, Marina

doi:10.18632/oncotarget.12944

Cited by 157 publications

(157 citation statements)

References 41 publications

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“…Although the glutamine dependence of some NSCLC cells is lost when they are grown in vivo , the canonical anaplerotic role of glutamine prevails in other contexts in vivo [9, 10, 12, 14–16, 30], and clinical trials of the GLS inhibitor CB-839 have yielded some promising results [8] suggesting that these recent observations in NSCLC models is certainly not general to all cancers. It is also important to note that the dispensability of glutamine in certain circumstances does not imply that anaplerosis in these cells is not required; as discussed above, cancer cells can find alternative ways to maintain an anaplerotic flux.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, many tumors rely on glutamine-mediated TCA cycle anaplerosis in vivo with concordance of glutamine dependence ex vivo and in vivo . (see Table 1), as discussed in detail below [9, 10, 12, 14, 15, 30] (Figure 2). Thus, recent observations in certain NSCLC mouse tumors cannot be generalized to other cancers.…”

Section: Culture Conditions and Model Systems Influence Glutamine Metmentioning

confidence: 99%

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Glutamine Metabolism in Cancer: Understanding the Heterogeneity

et al. 2017

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Reliance on glutamine has long been considered a hallmark of cancer cell metabolism. However, some recent studies have challenged this notion in vivo, prompting a need for further clarifications on the role of glutamine metabolism in cancer. We find that there is ample evidence of an essential role for glutamine in tumors and that a variety of factors, including tissue type, the underlying cancer genetics, the tumor microenvironment and other variables such as diet and host physiology collectively influence the role of glutamine in cancer. Thus the requirements for glutamine in cancer are overall highly heterogeneous. In this review, we discuss the implications both for basic science and for targeting glutamine metabolism in cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Culture Conditions and Model Systems Influence Glutamine Metmentioning

confidence: 99%

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

et al. 2017

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“…Several recent studies have shown that targeting glutamine uptake or metabolism can have anti-leukemic activity in AML 13,15,16,27,28 . However, most of these studies have focused on the role of glutamine in supporting energy metabolism rather on its role in maintaining redox homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Targeting glutamine metabolism and redox state for leukemia therapy

Gregory

Nemkov

Zaberezhnyy

et al. 2018

Preprint

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Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional genotoxic chemotherapy and a diagnosis of AML is usually fatal.More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. Here, we show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating acute lymphoblastic leukemia cells in vitro and in vivo. Thus, targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia. Key Points• Glutaminase inhibition commonly impairs glutathione metabolism and induces mitochondrial oxidative stress in acute myeloid leukemia cells • A glutaminase inhibitor synergizes with pro-oxidant drugs in inducing apoptosis and eliminating leukemia cells in vitro and in vivo Homoharringtonine (HHT; omacetaxine mepesuccinate), arsenic trioxide (ATO), cell-permeable glutathione reduced ethyl ester (GSH-MEE) and dimethyl 2oxoglutarate (α-ketoglutarate) were purchased from Millipore Sigma. Metabolic tracing experimentsCells were seeded at 3 x 10 5 /ml (replicates of 3) and treated with vehicle (DMSO) or CB-839 at 500 nM for 8 h, followed by incubation in glutamine-free RPMI 1640 supplemented with 13 C 5 , 15 N 2 -labeled L-glutamine (Cambridge Isotope Laboratories) for up to 12 h, in the presence of vehicle or drug. Flash frozen cell pellets (~ 1 x 10 6 cells) or supernatants (50 µl) were extracted and subjected to analysis by ultra-high pressure liquid chromatography and mass spectrometry (UHPLC/MS) as was previously described 20 . Metabolite assignments, isotopologue distributions, and correction for expected natural abundances of 13 C and 15 N isotopes were performed using MAVEN (Princeton University, Princeton, NJ) and manually validated. Cell viability assaysCells were seeded at 0.5-1.0 x10 5 /ml in triplicate wells of 48-well tissue culture plates. Where indicated, the cells were treated with drug for a period of 48-72 h.After treatment, a sample of cells from each well was stained with PI (10 µg/ml) and viable cells (PI -) were counted with a flow cytometer (Millipore Guava

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“…The human gastrointestinal tract is a main site of glutamate utilization with more than half of the glutamine obtained from systemic circulation utilized here. Glutamine has various effects on the structure and function of the tract and any change in glutamine metabolism may further cause the damage in gastrointestinal tract [45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Congenital Pouch Colon: Role of Genetics or Environmental Influence?

Mathur¹,

Nunia²,

Sharma³

et al. 2018

Pathobiology

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Background: Congenital pouch colon (CPC), a high type of anorectal malformation, is a sporadic disease and several environmental factors are known to be involved in its pathology. To the best of our knowledge, no familial incidence of CPC has been reported anywhere in the literature so far. Aim: In the present study, which is first of its kind, we have reported the familial incidences of CPC and also tried to elucidate the role of genetics in this pathology. Methods: We have reported 1 familial pedigree of CPC and 2 incidences of dizygotic twins (DZ), out of them one is affected and another one is normal. Highly comprehensive microarray CytoScan HD from Affymetrix was employed to understand the defects underlying submicroscopic genomic imbalance like segment duplication and deletion of the twin patients vis-à-vis their parents and unaffected siblings in these DZ twins. Results: A total of 21 copy number variations (CNVs) were reported in the patient samples that did not overlap with the CNVs in normal parents and healthy sibling, including 5 loss, 3 LOH and 13 gain with size varied from 95 bp to 77 kbp. Genetic analysis revealed involvement of 12 potential genetic loci on Chr 1, 2, 3, 4, 6, 11, and 16. Conclusion: Genetic study found that CPC could be a developmental disorder. These findings are important for further elucidating genetic causes of CPC pathogenesis.

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Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes

Cited by 157 publications

References 41 publications

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

Targeting glutamine metabolism and redox state for leukemia therapy

Congenital Pouch Colon: Role of Genetics or Environmental Influence?

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