Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

Jacque, Nathalie; Ronchetti, Anne Marie; Larrue, Clément; Meunier, Godelieve; Birsen, Rudy; Willems, Lise; Saland, Estelle; Decroocq, Justine; Maciel, Thiago; Lambert, Mireille; Poulain, Laury; Sujobert, Pierre; Joseph, Laure; Chapuis, Nicolas; Lacombe, Catherine; Moura, Ivan C.; Demo, Susan D.; Sarry, Jean Emmanuel; Récher, Christian; Mayeux, Patrick; Tamburini, Jérôme; Bouscary, Didier

doi:10.1182/blood-2015-01-621870

Cited by 332 publications

(299 citation statements)

References 39 publications

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“…Consistently, treatment of AML cell lines and AML primary cells with specific GLS inhibitors, such as CB-839 or BPTES, results in decreased cell viability and increased apoptosis. These results further reinforce the importance of glutaminolysis in AML reported by previous studies [2,3]. In addition,…”

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confidence: 81%

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2017

Oncotarget

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News on: Inhibiting glutaminase in acute myeloid leukemia: Metabolic dependency of selected AML subtypes by Polina Matre et al. Oncotarget. 2016; 7(48): 79722-79735. doi: 10.18632/oncotarget.12944. The fact that cancer cells rewire their metabolism to meet their extreme energetic and biosynthetic needs has long been known, since the seminal studies by Otto Warburg demonstrated that cancer cells heavily rely on glycolysis even in the presence of oxygen, the so-called Warburg effect. However, efforts to therapeutically target the special requirements of cancer cells have only gained traction in the last decades. In particular, beyond glycolysis and the Warburg effect, recent studies have highlighted a very prominent role for glutaminase (GLS) and glutamine metabolism in several types of hematological and solid tumors. Glutaminase is the ratelimiting enzyme in glutaminolysis and it is encoded by two different genes, GLS and GLS2. In turn, each of these encode for two different isoforms, kidney (KGA) and glutaminase C (GAC) for GLS, and liver (LGA) and glutaminase B (GAB) for GLS2. To further complicate the picture, different tissues express different levels of all these isoforms. In the current issue of Oncotarget, Matre et al. [1] comprehensively analyze the expression of GLS and GLUD1 (which catalyzes the second reaction in the glutaminolytic pathway) in AML. Their results suggest that AML cells preferentially express the GAC isoform of GLS, with much lower expression levels of the KGA isoform. Moreover, they find that AML cases with complex cytogenetics and certain AML molecular subtypes express the highest levels of GAC, suggesting that targeting glutaminolysis in these cases could be an effective therapeutic approach. Consistently, treatment of AML cell lines and AML primary cells with specific GLS inhibitors, such as CB-839 or BPTES, results in decreased cell viability and increased apoptosis. These results further reinforce the importance of glutaminolysis in AML reported by previous studies [2,3]. In addition, 13C and 15 N-isotope labeling experiments demonstrated that inhibition of GLS with CB-839 blocks glutamine utilization and results in decreased levels, and decreased isotope labeling of glutamate, aspartate and several TCA cycle intermediates. Moreover, and in line with a previous report [4], their results suggest that targeting glutaminolysis in AML cases harboring IDH1/IDH2 mutations could be a particularly attractive therapeutic approach. Thus, CB-839 treatment promoted cell growth arrest, reduced the levels of the oncometabolite 2-HG and promoted myeloid differentiation.This study adds up to previous literature that genetically demonstrated the therapeutic benefits of targeting glutaminase in different cancer types. Specifically, germinal loss of one Gls allele resulted in blunted tumor progression in a mouse model of hepatocellular carcinoma (HCC) [5]. Moreover, secondary deletion of both copies of Gls in already established tumors resulted in significant antileukemic effects, and highly sy...

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confidence: 81%

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2017

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“…Inhibiting GLS causes apoptosis through altered metabolism, with the effect exacerbated by inhibition of the anti-apoptotic protein BCL-2 53 .…”

Section: Oncogenic Change Role In Glutamine Metabolismmentioning

confidence: 99%

“…Given the many energy-generating and biosynthetic roles glutamine plays in growing cells, which are discussed and updated in this Review, inhibition of glutaminolysis has the potential to effectively target cancer cells. glutaminolytic flux in cancer 18,37,45,47,[52][53][54] . In contrast, the role of GLS2 in cancer seems more complex.…”

Section: Introductionmentioning

confidence: 99%

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

236

136

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The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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“…In addition, BCL-2 proteins might be more effectively inhibited by pan-Bcl-2 inhibitors that in contrast to ABT compounds block the expression of Mcl-1, an anti-apoptotic protein with a critical role in leukemic cell survival and drug resistance [115,116]. Since gluataminase inhibitors also cause mitochondrial apoptosis through an increase in glutamine level, an additional strategy to hinder mitochondrial oxidative phosphorylation might take advantage of the synergy between these drugs and ABT compounds [117]. Another intriguing possibility is to exploit hypoxia-activated prodrugs [81,118].…”

Section: Potential Targetsmentioning

confidence: 99%

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

et al. 2016

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A tight relationship between the acute myeloid leukemia (AML) population and the bone marrow (BM) microenvironment has been convincingly established. The AML clone contains leukemic stem cells (LSCs) that compete with normal hematopoietic stem cells (HSCs) for niche occupancy and remodel the niche; whereas, the BM microenvironment might promote AML development and progression not only through hypoxia and homing/adhesion molecules, but also through genetic defects. Although it is still unknown whether the niche influences treatment results or contains any potential target for treatment, this dynamic AML-niche interaction might be a promising therapeutic objective to significantly improve the AML cure rate.

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Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition

Cited by 332 publications

References 39 publications

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Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

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