
==== Front
Discov Oncol
Discov Oncol
Discover Oncology
2730-6011
Springer US New York

1245
10.1007/s12672-024-01245-0
Review
Glutamine and leukemia research: progress and clinical prospects
Wang Zexin wayen920326@163.com

Liu Miao
Yang Qiang
https://ror.org/00s528j33 grid.490255.f 0000 0004 7594 4364 Mianyang Central Hospital, Fucheng District, Mianyang, 621000 Sichuan China
31 8 2024
31 8 2024
12 2024
15 39125 3 2024
14 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Leukemia is an abnormal proliferation of white blood cells that occurs in bone marrow and expands through the blood. It arises from dysregulated differentiation, uncontrolled growth, and inhibition of apoptosis. Glutamine (GLN) is a "conditionally essential" amino acid that promotes growth and proliferation of leukemic cells. Recently, details about the role of GLN and its metabolism in the diagnosis and treatment of acute myeloid, chronic lymphocytic, and acute lymphoblastic leukemia have emerged. The uptake of GLN by leukemia cells and the dynamic changes of glutamine-related indexes in leukemia patients may be able to assist in determining whether the condition of leukemia is in a state of progression, remission or relapse. Utilizing the possible differences in GLN metabolism in different subtypes of leukemia may help to differentiate between different subtypes of leukemia, thus providing a basis for accurate diagnosis. Targeting GLN metabolism in leukemia requires simultaneous blockade of multiple metabolic pathways without interfering with the normal cellular and immune functions of the body to achieve effective leukemia therapy. The present review summarizes recent advances, possible applications, and clinical perspectives of GLN metabolism in leukemia. In particular, it focuses on the prospects of GLN metabolism in the diagnosis and treatment of acute myeloid leukemia. The review provides new directions and hints at potential roles for future clinical treatments and studies.

Keywords

Glutamine
Leukemia
Glutamine metabolism
Glutaminase
Glutamine transporter protein
issue-copyright-statement© Springer Science+Business Media, LLC 2024
==== Body
pmcIntroduction

Leukemias are a group of aggressive hematologic malignancies (also known as blood cancers) involving clonal proliferation of immature myeloid progenitor cells in the bone marrow and peripheral blood. They are caused by genetic mutations in hematopoietic stem cells. Presently, the treatment of choice includes chemotherapy and allogeneic stem cell transplantation [1]. With the development of time and technology, immunotherapeutic approaches for various leukemias have shown great promise, such as CD33 or CLL-1-specific chimeric antigen receptor (CAR)-T cell therapy[2, 3] and immune checkpoint inhibitor therapies such as TIM3, CD47, and anti-CD70 [4–6]. Regardless of therapy, relapse is common and shortens the survival of leukemia patients. Therefore, alternative treatment strategies are needed.

Growing evidence points to the critical role of amino acid metabolism on the diagnosis and treatment of leukemia. The metabolic pathways for GLN, arginine, isoleucine, tryptophan, cysteine, tyrosine, threonine, and L-serine play a crucial role in cancer. Moreover, amino acid metabolism is active in high-risk populations and the corresponding genes are associated with the immune microenvironment in acute myeloid leukemia (AML) patients [7]. Among the various amino acids, GLN metabolism seems to be an effective target against leukemia [8]. Leukemia cells have changes in the uptake and utilization of GLN as well as metabolic pathways. Through the dynamic changes of GLN-related indexes in patients can help to determine whether the leukemia is in progress, remission or relapse, and the differences in glutamine metabolism in different subtypes of leukemia can help to differentiate between subtypes of leukemia. Therefore, this review discusses the role of GLN metabolism in three common types of leukemia: AML, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia (ALL). Furthermore, it discusses the latest advances and developments in the field, as well as the therapeutic opportunities and challenges of GLN targeting.

Glutamine metabolism

GLN is a nonessential amino acid with two amino groups, the α-amino group and a readily hydrolysable side-chain amide group, with five carbons, a molecular weight of 146.15 kDa, and a chemical composition of C = 41.09%, H = 6.90%, O = 32.84%, and N = 19.17%. Classified as a neutral at physiological pH, it is the most abundant and versatile amino acid in the body (~ 0.6–0.8 mM) [9]. GLN is converted by glutaminase (GLS) to glutamate, which is then transformed to α-ketoglutarate (α-KG), an intermediate in the tricarboxylic acid (TCA) cycle and a core element in GLN metabolism [9, 10]. Glutamate can be directly converted to α-KG in two ways. The first is via glutamate dehydrogenase (GLDH), which produces the potential autophagy inducer ammonium and NADH or NADPH as cofactors. The second is via a group of transaminases, including glutamate–oxaloacetate transaminase, glutamate-pyruvate transaminase, and phosphoserine aminotransferase. Glutamate serves as a metabolite for the growth and proliferation of cancer cells via the TCA cycle. Moreover, glutamate can be deaminated in a number of reactions, thus providing a source of nitrogen for nonessential amino acids, purines and pyrimidines [11]. At the same time, intracellular glutathione (GSH) derived from GLN effectively scavenges intracellular reactive oxygen species (ROS), mediating ferroptosis and redox homeostasis in cancer cells [8]. Notably, GLN promotes the activation of rapamycin complex 1 (mTORC1), which is associated with apoptosis and autophagy in cancer cells.

GLN is as important in hematologic tumors as one of the nutrients on which cancer cells depend for survival. Given the need of tumor cells for glucose (for anaerobic glycolysis), GLN deficiency has been associated with cell death [12–14]. In both healthy and diseased states, immune cells consume as much GLN as possible, and its deprivation holds promise as a new therapeutic tool.

Glutaminase

GLS is a key enzyme involved in GLN metabolism. It comprises renal glutaminase-1 (GLS-1) and hepatic glutaminase-2 (GLS-2). GLS-1 has two variable splice isoforms: glutaminase C and renal glutaminase. The TCA cycle yields metabolic intermediates that are involved in the biosynthesis of nucleotides, GSH, and other amino acids [15]. In addition, GLN can be converted to α-KG for oxidative phosphorylation to produce ATP. Elevated expression of GLS-1 is directly or indirectly associated with poor prognosis in stem cell, colorectal, and breast cancers [16].

The GLS-2 gene is located on chromosome 12q13 and contains 18 coding exons. GLS-2 is considered more of a tumor suppressor than GLS-1. GLS-2 has been shown to be a p53 target as it contains two possible p53 binding sites [17]. The tumor suppressor p53 activates GLS-2 expression, regulates intracellular ROS levels and reduced/oxidized GSH ratios, and removes intracellular ROS to protect cells from genomic damage and ROS-sensitive apoptosis [18, 19]. TAp63, TAp73, and long-chain non-coding RNAs can also regulate GLS-2 [20–22]. Meanwhile, increased mitochondrial GLS expression enhances GLN catabolism by Myc oncogene inhibition of miR-23, which in turn targets GLS [23]. GLS inhibition decreases the production of GSH in AML cell lines, leading to increased mitochondrial ROS and apoptosis [8, 24]. Thus. GLS-1 and GLS-2 may serve as diagnostic and therapeutic targets for certain cancers. Clinical studies should explore new chemotherapeutic combinations of GLS inhibitors in the treatment of leukemia.

Inhibitors of the GLN transporter limit tumor demand for GLN

Strong expression of alanine-serine-cysteine transporter protein 2 (ASCT2), a GLN transporter, helps meet the amino acid needs of tumors [25] (Fig. 1). However, ASCT2 has also anticancer properties [26], because its deletion can lead to apoptosis of leukemia cells [27]. Inhibition of ASCT2-mediated GLN uptake in human cells using a lead compound (V-9302) resulted in attenuation of cancer cell growth and proliferation, frequent cell death, and increased oxidative stress [28]. ASCT2 plays the same role in cell proliferation and apoptosis in several cancers [29–36]. In a study of 25 patients with different clinically aggressive tumors (lung, breast, colon, or lymphoma), who underwent fluorine 18-(2S,4R)-4-fluoroglutamine positron emission tomography, all showed abnormal GLN metabolism [37]. Notably, ASCT2-mediated pharmacological inhibitors significantly reduced GLN uptake by triple-negative basal-like breast cancer cells, while having little effect on luminal breast cancer cells [38]. Taken together, this evidence implies that ASCT2 may serve as a potential target for antitumor drugs. ASCT2 inhibitors and the combination of ASCT2 inhibitors with other antitumor therapies may offer a promising antitumor strategy. However, more research is needed in this area of leukemia. Because GLN may be closely related to leukemogenesis and progression, it may directly or indirectly affect the diagnosis and treatment of leukemia.Fig. 1 Overview of glutamine metabolism in leukemia cells. The increased demand for glutamine by leukemia cells and simultaneous inhibition of the ASCT2 transporter, result in a declining hydrolysis of glutamine to glutamate. α-KG, α-ketoglutarate; ASCT2, alanine-serine-cysteine transporter protein 2; GLS, glutaminase; TCA, tricarboxylic acid. The Illustration was created in Figdraw

GLN metabolism in leukemia

Leukemia is a myeloid malignancy characterized by abnormal proliferation and differentiation of hematopoietic precursor cells. Cancer cells are highly dependent on GLN metabolism and availability [39]. GLN metabolism is centered in the mitochondria. Mitochondria play a crucial role in the maintenance of hematopoietic stem cells, whose malignant transformation ultimately leads to leukemic stem cells [40]. The first evidence of impaired mitochondrial metabolism in AML was the presence of mutations in the gene encoding isocitrate dehydrogenase (IDH) in AML patients [41, 42].

Recent in vivo and in vitro studies have shown that GLN is restricted to the cancer cell environment [43]. Glutamine is used as an alternative fuel for the TCA cycle, with plasma concentrations of 0.6–0.8 mM, and is the most common amino acid in blood [9, 10]. As in other cancers, plasma GLN concentrations in AML patients are quite low, 0.3 mM or less, suggesting that GLN is rapidly depleted in AML cells [10, 44, 45]. A study of 55 newly diagnosed AML patients and 45 healthy individuals also showed that GLN levels were much lower in the former than in the latter [46]. AML cells are completely dependent on exogenous GLN, and knockdown of high-affinity ASCT2 leads to apoptosis in AML cell lines and inhibits tumor progression in AML xenografts and primary AML mouse models [47] Indeed, ASCT2 plays pleiotropic roles in cellular metabolism and serves as a promising molecular target for the treatment of leukemia [27].

GLS is a rate-limiting factor for TCA activity in AML and is highly expressed in AML patients [48]. The initial step required for glucose-independent oxidative phosphorylation is the conversion of GLN to glutamate. Subsequently, glutamate provides the substrate for the synthesis of α-KG. IDH catalyzes the oxidative decarboxylation of isocitrate to α-KG. Mutations in IDH result in the conversion of α-KG to R2-hydroxyglutarate, which is detected in approximately 2% of adult AML patients [42, 49] (Fig. 2). ATP and metabolic pathways localized to the mitochondria have been shown to play an important role in the progression of AML [50]. Elevated levels of 2-hydroxyglutarate, a metabolite associated with the TCA cycle, may promote tumorigenesis [51]. Meanwhile, the central nervous system is also involved in metabolic processes, posing a major challenge to the treatment of acute leukemia [52]. In addition, in studies on GLN metabolism, N6-methyladenosine (m6A) regulates GLN metabolism through modification of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which directly or indirectly promotes AML cell development and self-renewal, and higher levels of IGF2BP2 expression correlate with a poor prognosis for AML [53].Fig. 2 Strategies for targeting glutamine metabolism in AML. l-asparaginase allows the hydrolysis of extracellular glutamine, impeding its synthesis and hydrolysis. Upon translocation to the cell, glutamine is transformed to glutamate by the two isoforms of glutaminase, GLS-1 and GLS-2. Glutamine is synthesized from glutamate and ammonia (NH3) by glutamine synthetase. In this reaction, an ATP is consumed. The reverse reaction yields glutamate and ammonium ions (NH4+). Almost all cells in the body contain glutamine and ammonium ions, and express both glutamine synthetase and GLS. The predominant expression of one or the other of these enzymes will determine whether tissues are more likely to produce or consume glutamine. α-KG, α-ketoglutarate; ASCT2, alanine-serine-cysteine transporter protein 2; GLS, glutaminase; GSH, glutathione; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; TCA, tricarboxylic acid; XCT, cystine/glutamate transporter

Taken together, changes in glutamine utilization and metabolic pathways in leukemia cells are expected to be potential prognostic markers. For example, GLS is highly expressed in AML patients and IGF2BP2 is associated with prognosis in AML. By detecting dynamic changes in glutamine-related markers, it is possible to understand the progression, remission or relapse of leukemia and provide diagnostic value. Glutaminolysis inhibits the conversion of GLN to circulating TCA metabolites by regulating various enzymes, and GLS is the first step in the process. Therefore, targeting GLS to block GLN degradation is a promising therapeutic strategy. Targeting of the two GLS isoforms, GLS-1 and GLS-2, will provide new insights on the treatment of leukemia. Hereafter, we discuss the relationship between GLN and AML, CLL, and ALL.

Glutamine as a therapeutic strategy for leukemia

Acute myeloid leukemia

Reducing intracellular GLN levels in AML patients is one of the main strategies for AML treatment. The most important step in targeting GLN is the use of GLS to catalyze the deamination reaction of GLN to glutamate. Glutamate is further catabolized and metabolized to α-KG which feeds into the TCA cycle to provide energy. Therefore, glutaminase inhibitors are a popular antitumor strategy [54]. In particular, the renal-type GLS-1 form disrupts GLN-driven oxidative phosphorylation in AML cell lines, thereby preventing tumor growth and inducing apoptosis [55].

Blocking GLN metabolism with the GLS inhibitor CB-839 results in GSH depletion [56, 57]. In AML, where GSH acts as an antioxidant, a decrease in GSH leads to the accumulation of mitochondrial ROS and subsequent apoptosis [58, 59]. At the same time, the inhibitory effect of CB-839 makes AML cells more sensitive to adjuvants of the mitochondrial redox state, such as arsenic trioxide and hypertriglyceride [8]. Therefore, CB-839 applied together with the above adjuvants induces apoptosis in AML cells. In addition to inducing apoptosis in AML cells, CB-839 inhibits also the mTOR signaling pathway [54]. In AML cells, GLN condenses with cysteine and glycine to produce GSH, which maintains redox homeostasis, prevents ROS-induced damage, and provides a nitrogen source for DNA replication [55, 60]. In addition, many AML gene mutations have been shown to be associated with a number of mutations. In addition, many AML gene mutants are specific for GLN metabolism. For example, the glutaminase inhibitor BPTES was able to target and inhibit the unique metabolic profile of primary AML cells with IDH mutations (i.e., glutamine addiction), which in turn slowed the growth of primary AML cells with mutant IDH [49]. The fact that there is a unique selective inhibitory effect of interfering with glutamine metabolism on AML cells with IDH mutations is demonstrated. Other than this, aberrant expression of the FMS-like tyrosine kinase 3 (FLT3) gene in AML also leads to disorders of glutamate metabolism [61]. Approximately 25–30% of AML cases show hyperactivation due to mutations in tandem duplications within genes (FLT3–ITD) or in the structural domain of tyrosine kinase (FLT3–TKD) [62]. The FLT3 inhibitor AC220 (also known as Quizartinib) decreases GLN uptake and GSH production in AML cells, while increasing sensitivity to oxidative stress [63]. In addition, GLN is also used as a parenteral nutrient to assist in the treatment of AML. In a randomized, double-blind, controlled study including 45 adult AML patients and 127 cycles of chemotherapy, GLN improved the clinical course of patients after bone marrow transplantation and parenteral nutrition [64]. If in AML, the degree of GLN dependence of AML cells with specific gene mutations (e.g. IDH mutations and FLT3 mutations) is investigated. It is possible to assist in the diagnosis of such subtypes of AML with specific gene mutations by detecting GLN-related metabolic markers.

At present, the specific quantitative indicators and the exact extent of GLN dependence in AML subtypes with specific genetic mutations need to be investigated in further studies. In general, however, this dependence may be manifested by an increased rate of cellular uptake and utilization of GLN, increased activity of enzymes involved in intracellular GLN metabolism, and a more critical role of the GLN pathway in maintaining cell survival, proliferation, and energy supply. In conclusion, GLN is essential for the treatment of leukemia and is an effective therapeutic strategy. It is also important in medical research as a nutrient to support cell growth and repair, and as a potential antitumor agent for the treatment of leukemia.

Chronic lymphocytic leukemia

The 13q deletion is the most common cytogenetic mutation in CLL. Bruton’s tyrosine kinase and B-cell lymphoma-2 inhibitors are widely used in the clinic for the treatment of CLL; however, CLL cells have developed resistance to these drugs. CB-839, a small-molecule GLS-1 inhibitor, decreases GLS-1 activity and inhibits CLL cell proliferation; however, the efficacy of CB-839 is limited in combination with conventional CLL drugs [65]. In addition, CLL lymphocytes in del11q-positive CLL cells exhibit altered glutamine metabolism [66]. Mitochondria in CLL have been reported to increase ROS production [67]. The role of GLN in preventing the overproduction of ROS underscores its importance in tumor growth and energy production [68].

Acute lymphoblastic leukemia

Acute lymphoblastic leukemia is a heterogeneous malignancy of immature B or T lymphoblastoid cells that is most prevalent in children [69, 70]. l-asparaginase (ASNase) is the first-line therapy for childhood ALL [71, 72], as well as adult ALL [73]. ASNase hydrolyzes GLN to produce glutamate and may be considered for patients with Notch1 ALL positivity [74]. The notch1 receptor is effective in the treatment of ALL. Notably, when GLN is secreted by adipocytes, its cytotoxicity towards ALL cells is blocked [75]. Therefore, targeting GLN and ASNase may also serve in the development of novel therapeutic agents [76, 77]. In addition, GLN nutritional therapy during chemotherapy can effectively improve and enhance the systemic nutritional status and immunity of pediatric patients with ALL [78]. Notably, there are genomic differences in relapsed ALL during treatment [79]. Among these differences, reduced dependence on GLN is an important cause of drug resistance in leukemia cells [80].

Mitochondria are one of the major sources of ROS production. Redox dysfunction plays a crucial role in leukemogenesis in ALL, and inhibition of ROS production via NADPH oxidases is a novel therapeutic tool for the treatment of ALL [81]. Many enzymes neutralize ROS, including superoxide dismutase, catalase, glutathione peroxidase (GPX), thioredoxin, peroxiredoxin, and glutathione transferase [82]. In addition, activating mutations in NOTCH1 are common in T-cell ALL, and inhibition of NOTCH1 signaling suppresses and promotes autophagy during GLN catabolism [83]. GLN metabolism regulates the expression of mitochondrial uncoupling protein 2 (UCP2) in T-cell ALL cell lines, and UCP2 is required for T-cell ALL proliferation [84]. A link between UCP2 and ROS production has been demonstrated [85]. Therefore, promoting GSH production by blocking GLN metabolism and indirectly preventing ROS production is a novel therapeutic strategy for ALL.

GLN causes cellular ferroptosis in an indirect way

In clinical settings, radiotherapy remains the mainstay treatment for leukemia, although GLN-targeting agents (e.g., CB-839) have been developed to indirectly induce ROS production [8]. It is well known that ROS production and lipid peroxidation is a key feature and an important step in iron death, and the generation of ROS promotes lipid peroxidation, which in turn triggers iron death. However, the mechanism of iron death involves a variety of factors, including antioxidant system factors, such as GSH and GPX4, which are important mechanisms of iron death [86, 87]; iron metabolism factors, such as Fe2+ which promotes the production of ROS through the Fenton reaction and so on, which in turn promotes lipid peroxidation [88]; lipid metabolism-related factors, such as lipoxygenase enzymes (LOXs), which can directly oxidize unsaturated fatty acids on biological membranes (PUFAs) and PUFA-containing lipids on biological membranes, which may induce iron death [87]; signaling pathway factors, such as cystathionine-glutamate transporter receptor (system Xc -), p53, and other pathways can regulate iron death. The mechanism underlying the role of GLN in leukemia remains unclear, and its use in clinical practice is relatively rare. Notably, p53-dependent activation of GLS-2 expression correlates with ROS, while elevated ROS levels lead to p53 stabilization and activation [89]. Sawako et al. demonstrated that GLS-2 reduces cellular sensitivity to ROS-related apoptosis [19]. Increased mitochondrial production of ROS and lipid peroxidation, along with decreased expression of GSH and GPX4, lead to ferroptosis [90, 91]. The accumulation of intracellular iron during ferroptosis is important in leukemic cells. GLN metabolism enhances ROS production in the TCA cycle [92–94]. GLN catabolism inhibits intracellular GSH depletion and subsequent ROS generation [49, 95], as well as affecting the TCA cycle [96]. The accumulation of lipid ROS can lead to ferroptosis [96]. Notably, GLS-2 is present on the cell surface of human neutrophils [97], which promotes lipid ROS production and enhances ferroptosis by catalyzing the generation of α-KG from glutamate [98, 99]. GLN increases α-KG levels and can activate amino acid sensor kinases, leading to formation of mTORC1 [100, 101], which then regulates ferroptosis sensitivity [102, 103]. In conclusion, increasing ROS levels through GLN metabolism promotes ferroptosis by blocking GSH synthesis (Fig. 3), which may provide new therapeutic guidelines for ferroptosis-based clinical treatment.Fig. 3 Glutamine induces ferroptosis. α-KG, α-ketoglutarate; ASCT2, alanine-serine-cysteine transporter protein 2; GLS, glutaminase; GPX4, glutathione peroxidase 4; GSH, glutathione; OXPHOS, oxidative phosphorylation; PLs, phospholipids; PUFA, polyunsaturated fatty acids; ROS, reactive oxygen species; TCA, tricarboxylic acid; XCT, cystine/glutamate transporter

Discussion

GLN and its metabolites have significant antileukemic effects. Because of the close association between GLN and leukemia prognosis, we have summarized the latest developments on GLN and leukemia-related drugs or other studies by publication date (in no particular order), category, and content (Table 1). Table 1 GLN and leukemia-related drug development and other sustainability studies

Published	Category	Drugs and other substances	
2021	Glutamine uptake inhibitors	V-9302 [104, 105]	
2019	Glutamine transporter	SLC38A1 [106]	
2019	Glutamine uptake inhibitors	GPNA [106, 107]	
2018	Asparaginase	Erwinaze [108]	
2019–2023	Glutaminase inhibitors	CB-839 [65, 109, 110]	
2019	Glutaminase antagonists	DON [111]	
2019	Glutaminase antagonists	JHU-083 [112]	
2021	Glutaminase inhibitors	Gilteritinib [109]	
2021	Asparaginase	Pegcrisantaspase [113]	
2019	Asparaginase	ASNase [114]	
1982	Glutaminase inhibitors	l-glutamine antagonist [115]	
Owing to the limitations of GLN-related drugs and inhibitors of GLN metabolism in clinical trials, they should be used with caution in clinical settings

There are multiple pathways involving GLN in leukemia, along with multiple factors that regulate and interfere with each pathway. GLN metabolic pathway: Supplies carbon for TCA cycle intermediates and nitrogen for nucleotide and amino acid biosynthesis, and plays an important role in hematopoietic tumors and hematologic neoplasms [116]; Bypass pathway: when leukemia cells are deprived of Gln, the serine pathway upregulates the key serine enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoribosyltransferase (PSAT), leading to an increased demand for serine and exacerbation of serine dependence in leukemia cells [117]; Lipid-related metabolism: AML cells are dependent on OXPHOS [118–120], AML cells obtain free fatty acids from bone marrow adipocytes and utilize fatty acid oxidation (FAO) and OXPHOS to maintain AML cell survival and growth [121–123]. However, OXPHOS-deficient cells accelerate the utilization of GLN, and GLN depletion promotes the accumulation of ROS [124]. We also note that targeting GLN and GLN metabolism (or parts of it) may have a limited impact on leukemia therapy. For example, ASCT2 is not the sole transporter for GLN [125]. This suggests that GLN influences the development and progression of leukemia. Therefore, future studies related to GLN should focus on the inhibition of multiple metabolic pathways for the effective treatment of leukemia.

Research on human leukemia therapy and GLN continues. The body's immune cells are also the focus of our interference with GLN, both in terms of the dependence of cancer cells on GLN and as a component of the TCA cycle. For example, immune cells use GLN to grow rapidly and gain immunity [126]. Reprogrammed GLN metabolism plays an important role in the antitumor immune response of immune cells, such as T cells, B cells, macrophages, and natural killer cells [127]. Parenteral GLN supplements may be relevant in the anti-tumor immune response, as they enhance neutrophil phagocytosis and maintain the nutritional status [128]. Inhibition of GLN metabolism can lead to immune escape for cancer cells, as observed with the GLN inhibitor V-9302 in human breast cancer cells [129]. Therefore, further experiments should be conducted to determine whether GLN inhibitors and related drugs disrupt the anticancer effects of immune cells in the bone marrow microenvironment during diagnosis and treatment. Targeting GLN metabolism in cancer cells without interfering with the immune response is a major challenge for future research.

Conclusion

Existing evidence points to the attractiveness of GLN as a new target for the treatment of leukemia. This strategy is already exemplified by CB-839 and V-9302, but includes also mTOR signaling and apoptosis in AML cells. Expression of an abnormal gene (FLT3) can cause GLN metabolic disorders. In addition, GLN plays an important role in CLL and ALL. The key enzyme in GLN metabolism is the GLS-2 isoform, which acts as a tumor suppressor. It activates and promotes hepatic glutamine catabolism and triggers the activation of mTORC1, a signal that also controls ferroptosis.

Inhibitors of GLN metabolism have also some limitations in the treatment of leukemia. First, a clear framework for clinical care has not been established, and there is a lack of additional empirical support for the use of GLN inhibitors to improve the prognosis of leukemia. More experimental studies are needed to provide better empirical data to improve the prognostic gap in GLN treatment of leukemia. Second, numerous studies have been conducted on AML, while relatively few have considered other types of leukemia (including, but not limited to, leukemia with rare genotypes and phenotypes). Such studies could determine whether the mechanism of action is the same in AML as in other types of leukemia.

In conclusion, available studies suggest that GLN is an attractive new strategy for the treatment of leukemia.

Future directions

The study of GLN in leukemia is in its preliminary stages, and its mechanism of action and clinical applications need further investigation. Future studies can focus on the following aspects: (1) the regulatory effect of GLN on various functional molecules in leukemia cells, (2) the regulatory mechanism of GLN on the relevant functional molecules in leukemia cells, (3) the application of GLN in leukemia treatment, (4) the effects of GLN on leukemia cell functions, such as cellular energy supply mechanisms, essential molecules, intracellular redox homeostasis mechanisms, and related signaling pathways for survival and proliferation, and (5) the effect of GLN on the prognosis of leukemia patients. The accrued knowledge will provide a new perspective for the effective clinical treatment of different types of leukemia.

Acknowledgements

We thank Editage (www.editage.com) for their editing support on this manuscript.

Author contributions

W.Z. wrote and structured the paper; W.Z. analyzed literature data and wrote the paper; Y.Q. and L.M. reviewed the literature; all authors have read and agreed to the published version of the manuscript.

Funding

No funding was received to assist with the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Pollyea DA Bixby D Perl A Bhatt VR Altman JK Appelbaum FR de Lima M Fathi AT Foran JM Gojo I Hall AC Jacoby M Lancet J Mannis G Marcucci G Martin MG Mims A Neff J Nejati R Olin R Percival M-E Prebet T Przespolewski A Rao D Ravandi-Kashani F Shami PJ Stone RM Strickland SA Sweet K Vachhani P Wieduwilt M Gregory KM Ogba N Tallman MS NCCN guidelines insights: acute myeloid leukemia, Version 2.2021 J Natl Compr Cancer Netw JNCCN 2021 19 16 27 10.6004/jnccn.2021.0002 33406488
Pollyea DA, Bixby D, Perl A, Bhatt VR, Altman JK, Appelbaum FR, de Lima M, Fathi AT, Foran JM, Gojo I, Hall AC, Jacoby M, Lancet J, Mannis G, Marcucci G, Martin MG, Mims A, Neff J, Nejati R, Olin R, Percival M-E, Prebet T, Przespolewski A, Rao D, Ravandi-Kashani F, Shami PJ, Stone RM, Strickland SA, Sweet K, Vachhani P, Wieduwilt M, Gregory KM, Ogba N, Tallman MS. NCCN guidelines insights: acute myeloid leukemia, Version 2.2021. J Natl Compr Cancer Netw JNCCN. 2021;19:16–27. 10.6004/jnccn.2021.0002.33406488 10.6004/jnccn.2021.0002
2. Jin X Zhang M Sun R Lyu H Xiao X Zhang X Li F Xie D Xiong X Wang J Lu W Zhang H Zhao M First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia J Hematol OncolJ Hematol Oncol 2022 15 88 10.1186/s13045-022-01308-1 35799191
Jin X, Zhang M, Sun R, Lyu H, Xiao X, Zhang X, Li F, Xie D, Xiong X, Wang J, Lu W, Zhang H, Zhao M. First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia. J Hematol OncolJ Hematol Oncol. 2022;15:88. 10.1186/s13045-022-01308-1.35799191 10.1186/s13045-022-01308-1
3. Wang Q Wang Y Lv H Han Q Fan H Guo B Wang L Han W Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia Mol Ther 2015 23 184 191 10.1038/mt.2014.164 25174587
Wang Q, Wang Y, Lv H, Han Q, Fan H, Guo B, Wang L, Han W. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Mol Ther. 2015;23:184–91. 10.1038/mt.2014.164.25174587 10.1038/mt.2014.164
4. Gallazzi M Ucciero MAM Faraci DG Mahmoud AM Al Essa W Gaidano G Mouhssine S Crisà E New frontiers in monoclonal antibodies for the targeted therapy of acute myeloid leukemia and myelodysplastic syndromes Int J Mol Sci 2022 23 7542 10.3390/ijms23147542 35886899
Gallazzi M, Ucciero MAM, Faraci DG, Mahmoud AM, Al Essa W, Gaidano G, Mouhssine S, Crisà E. New frontiers in monoclonal antibodies for the targeted therapy of acute myeloid leukemia and myelodysplastic syndromes. Int J Mol Sci. 2022;23:7542. 10.3390/ijms23147542.35886899 10.3390/ijms23147542
5. Abaza Y Zeidan AM Immune checkpoint inhibition in acute myeloid leukemia and myelodysplastic syndromes Cells 2022 11 2249 10.3390/cells11142249 35883692
Abaza Y, Zeidan AM. Immune checkpoint inhibition in acute myeloid leukemia and myelodysplastic syndromes. Cells. 2022;11:2249. 10.3390/cells11142249.35883692 10.3390/cells11142249
6. Riether C Pabst T Höpner S Bacher U Hinterbrandner M Banz Y Müller R Manz MG Gharib WH Francisco D Bruggmann R van Rompaey L Moshir M Delahaye T Gandini D Erzeel E Hultberg A Fung S de Haard H Leupin N Ochsenbein AF Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents Nat Med 2020 26 1459 1467 10.1038/s41591-020-0910-8 32601337
Riether C, Pabst T, Höpner S, Bacher U, Hinterbrandner M, Banz Y, Müller R, Manz MG, Gharib WH, Francisco D, Bruggmann R, van Rompaey L, Moshir M, Delahaye T, Gandini D, Erzeel E, Hultberg A, Fung S, de Haard H, Leupin N, Ochsenbein AF. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med. 2020;26:1459–67. 10.1038/s41591-020-0910-8.32601337 10.1038/s41591-020-0910-8
7. Zhou H Wang F Niu T Prediction of prognosis and immunotherapy response of amino acid metabolism genes in acute myeloid leukemia Front Nutr 2022 9 1056648 10.3389/fnut.2022.1056648 36618700
Zhou H, Wang F, Niu T. Prediction of prognosis and immunotherapy response of amino acid metabolism genes in acute myeloid leukemia. Front Nutr. 2022;9:1056648. 10.3389/fnut.2022.1056648.36618700 10.3389/fnut.2022.1056648
8. Gregory MA Nemkov T Park HJ Zaberezhnyy V Gehrke S Adane B Jordan CT Hansen KC D’Alessandro A DeGregori J Targeting glutamine metabolism and redox state for leukemia therapy Clin Cancer Res Off J Am Assoc Cancer Res 2019 25 4079 4090 10.1158/1078-0432.CCR-18-3223
Gregory MA, Nemkov T, Park HJ, Zaberezhnyy V, Gehrke S, Adane B, Jordan CT, Hansen KC, D’Alessandro A, DeGregori J. Targeting glutamine metabolism and redox state for leukemia therapy. Clin Cancer Res Off J Am Assoc Cancer Res. 2019;25:4079–90. 10.1158/1078-0432.CCR-18-3223.10.1158/1078-0432.CCR-18-3223
9. Yang L Venneti S Nagrath D Glutaminolysis: a hallmark of cancer metabolism Annu Rev Biomed Eng 2017 19 163 194 10.1146/annurev-bioeng-071516-044546 28301735
Yang L, Venneti S, Nagrath D. Glutaminolysis: a hallmark of cancer metabolism. Annu Rev Biomed Eng. 2017;19:163–94. 10.1146/annurev-bioeng-071516-044546.28301735 10.1146/annurev-bioeng-071516-044546
10. Darmaun D Matthews DE Bier DM Glutamine and glutamate kinetics in humans Am J Physiol 1986 251 E117 126 10.1152/ajpendo.1986.251.1.E117 2873746
Darmaun D, Matthews DE, Bier DM. Glutamine and glutamate kinetics in humans. Am J Physiol. 1986;251:E117-126. 10.1152/ajpendo.1986.251.1.E117.2873746 10.1152/ajpendo.1986.251.1.E117
11. Rex MR Williams R Birsoy K Ta Llman MS Stahl M Targeting mitochondrial metabolism in acute myeloid leukemia Leuk Lymphoma 2022 63 530 537 10.1080/10428194.2021.1992759 34704521
Rex MR, Williams R, Birsoy K, Ta Llman MS, Stahl M. Targeting mitochondrial metabolism in acute myeloid leukemia. Leuk Lymphoma. 2022;63:530–7. 10.1080/10428194.2021.1992759.34704521 10.1080/10428194.2021.1992759
12. Wang M Zhao A Li M Niu T Amino acids in hematologic malignancies: current status and future perspective Front Nutr 2023 10 1113228 10.3389/fnut.2023.1113228 37032776
Wang M, Zhao A, Li M, Niu T. Amino acids in hematologic malignancies: current status and future perspective. Front Nutr. 2023;10:1113228. 10.3389/fnut.2023.1113228.37032776 10.3389/fnut.2023.1113228
13. Emadi A Exploiting AML vulnerability: glutamine dependency Blood 2015 126 1269 1270 10.1182/blood-2015-07-659508 26359432
Emadi A. Exploiting AML vulnerability: glutamine dependency. Blood. 2015;126:1269–70. 10.1182/blood-2015-07-659508.26359432 10.1182/blood-2015-07-659508
14. Petronini PG Urbani S Alfieri R Borghetti AF Guidotti GG Cell susceptibility to apoptosis by glutamine deprivation and rescue: survival and apoptotic death in cultured lymphoma-leukemia cell lines J Cell Physiol 1996 169 175 185 10.1002/(SICI)1097-4652(199610)169:1<175::AID-JCP18>3.0.CO;2-C 8841434
Petronini PG, Urbani S, Alfieri R, Borghetti AF, Guidotti GG. Cell susceptibility to apoptosis by glutamine deprivation and rescue: survival and apoptotic death in cultured lymphoma-leukemia cell lines. J Cell Physiol. 1996;169:175–85. 10.1002/(SICI)1097-4652(199610)169:1%3c175::AID-JCP18%3e3.0.CO;2-C.8841434 10.1002/(SICI)1097-4652(199610)169:1<175::AID-JCP18>3.0.CO;2-C
15. Schulze A Harris AL How cancer metabolism is tuned for proliferation and vulnerable to disruption Nature 2012 491 364 373 10.1038/nature11706 23151579
Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491:364–73. 10.1038/nature11706.23151579 10.1038/nature11706
16. Saha SK Islam SMR Abdullah-AL-Wadud M Islam S Ali F Park KS Multiomics analysis reveals that GLS and GLS2 differentially modulate the clinical outcomes of cancer J Clin Med 2019 8 355 10.3390/jcm8030355 30871151
Saha SK, Islam SMR, Abdullah-AL-Wadud M, Islam S, Ali F, Park KS. Multiomics analysis reveals that GLS and GLS2 differentially modulate the clinical outcomes of cancer. J Clin Med. 2019;8:355. 10.3390/jcm8030355.30871151 10.3390/jcm8030355
17. Hu W Zhang C Wu R Sun Y Levine A Feng Z Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function Proc Natl Acad Sci USA 2010 107 7455 7460 10.1073/pnas.1001006107 20378837
Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA. 2010;107:7455–60. 10.1073/pnas.1001006107.20378837 10.1073/pnas.1001006107
18. Lane DP Cancer. p53, guardian of the genome Nature 1992 358 15 16 10.1038/358015a0 1614522
Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358:15–6. 10.1038/358015a0.1614522 10.1038/358015a0
19. Suzuki S Tanaka T Poyurovsky MV Nagano H Mayama T Ohkubo S Lokshin M Hosokawa H Nakayama T Suzuki Y Sugano S Sato E Nagao T Yokote K Tatsuno I Prives C Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species Proc Natl Acad Sci USA 2010 107 7461 7466 10.1073/pnas.1002459107 20351271
Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, Sugano S, Sato E, Nagao T, Yokote K, Tatsuno I, Prives C. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA. 2010;107:7461–6. 10.1073/pnas.1002459107.20351271 10.1073/pnas.1002459107
20. Giacobbe A Bongiorno-Borbone L Bernassola F Terrinoni A Markert EK Levine AJ Feng Z Agostini M Zolla L Agrò AF Notterman DA Melino G Peschiaroli A p63 regulates glutaminase 2 expression Cell Cycle 2013 12 1395 1405 10.4161/cc.24478 23574722
Giacobbe A, Bongiorno-Borbone L, Bernassola F, Terrinoni A, Markert EK, Levine AJ, Feng Z, Agostini M, Zolla L, Agrò AF, Notterman DA, Melino G, Peschiaroli A. p63 regulates glutaminase 2 expression. Cell Cycle. 2013;12:1395–405. 10.4161/cc.24478.23574722 10.4161/cc.24478
21. Velletri T Romeo F Tucci P Peschiaroli A Annicchiarico-Petruzzelli M Niklison-Chirou MV Amelio I Knight RA Mak TW Melino G Agostini M GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation Cell Cycle 2013 12 3564 3573 10.4161/cc.26771 24121663
Velletri T, Romeo F, Tucci P, Peschiaroli A, Annicchiarico-Petruzzelli M, Niklison-Chirou MV, Amelio I, Knight RA, Mak TW, Melino G, Agostini M. GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation. Cell Cycle. 2013;12:3564–73. 10.4161/cc.26771.24121663 10.4161/cc.26771
22. Hung C-L Wang L-Y Yu Y-L Chen H-W Srivastava S Petrovics G Kung H-J A long noncoding RNA connects c-Myc to tumor metabolism Proc Natl Acad Sci USA 2014 111 18697 18702 10.1073/pnas.1415669112 25512540
Hung C-L, Wang L-Y, Yu Y-L, Chen H-W, Srivastava S, Petrovics G, Kung H-J. A long noncoding RNA connects c-Myc to tumor metabolism. Proc Natl Acad Sci USA. 2014;111:18697–702. 10.1073/pnas.1415669112.25512540 10.1073/pnas.1415669112
23. Gao P Tchernyshyov I Chang T-C Lee Y-S Kita K Ochi T Zeller K De Marzo AM Van Eyk JE Mendell JT Dang CV c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism Nature 2009 458 762 765 10.1038/nature07823 19219026
Gao P, Tchernyshyov I, Chang T-C, Lee Y-S, Kita K, Ochi T, Zeller K, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism. Nature. 2009;458:762–5. 10.1038/nature07823.19219026 10.1038/nature07823
24. Dernie F Characterisation of a mitochondrial glutamine transporter provides a new opportunity for targeting glutamine metabolism in acute myeloid leukaemia Blood Cells Mol Dis 2021 88 102422 10.1016/j.bcmd.2020.102422 32197941
Dernie F. Characterisation of a mitochondrial glutamine transporter provides a new opportunity for targeting glutamine metabolism in acute myeloid leukaemia. Blood Cells Mol Dis. 2021;88: 102422. 10.1016/j.bcmd.2020.102422.32197941 10.1016/j.bcmd.2020.102422
25. Cormerais Y Massard PA Vucetic M Giuliano S Tambutté E Durivault J Vial V Endou H Wempe MF Parks SK Pouyssegur J The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5) J Biol Chem 2018 293 2877 2887 10.1074/jbc.RA117.001342 29326164
Cormerais Y, Massard PA, Vucetic M, Giuliano S, Tambutté E, Durivault J, Vial V, Endou H, Wempe MF, Parks SK, Pouyssegur J. The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5). J Biol Chem. 2018;293:2877–87. 10.1074/jbc.RA117.001342.29326164 10.1074/jbc.RA117.001342
26. Teixeira E Silva C Martel F The role of the glutamine transporter ASCT2 in antineoplastic therapy Cancer Chemother Pharmacol 2021 87 447 464 10.1007/s00280-020-04218-6 33464409
Teixeira E, Silva C, Martel F. The role of the glutamine transporter ASCT2 in antineoplastic therapy. Cancer Chemother Pharmacol. 2021;87:447–64. 10.1007/s00280-020-04218-6.33464409 10.1007/s00280-020-04218-6
27. Ni F Yu W-M Li Z Graham DK Jin L Kang S Rossi MR Li S Broxmeyer HE Qu C-K Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression Nat Metab 2019 1 390 403 10.1038/s42255-019-0039-6 31535081
Ni F, Yu W-M, Li Z, Graham DK, Jin L, Kang S, Rossi MR, Li S, Broxmeyer HE, Qu C-K. Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression. Nat Metab. 2019;1:390–403. 10.1038/s42255-019-0039-6.31535081 10.1038/s42255-019-0039-6
28. Schulte ML Fu A Zhao P Li J Geng L Smith ST Kondo J Coffey RJ Johnson MO Rathmell JC Sharick JT Skala MC Smith JA Berlin J Washington MK Nickels ML Manning HC Pharmacological blockade of ASCT2-dependent glutamine transport leads to anti-tumor efficacy in preclinical models Nat Med 2018 24 194 202 10.1038/nm.4464 29334372
Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, Kondo J, Coffey RJ, Johnson MO, Rathmell JC, Sharick JT, Skala MC, Smith JA, Berlin J, Washington MK, Nickels ML, Manning HC. Pharmacological blockade of ASCT2-dependent glutamine transport leads to anti-tumor efficacy in preclinical models. Nat Med. 2018;24:194–202. 10.1038/nm.4464.29334372 10.1038/nm.4464
29. Huang F Zhao Y Zhao J Wu S Jiang Y Ma H Zhang T Upregulated SLC1A5 promotes cell growth and survival in colorectal cancer Int J Clin Exp Pathol 2014 7 6006 6014 25337245
Huang F, Zhao Y, Zhao J, Wu S, Jiang Y, Ma H, Zhang T. Upregulated SLC1A5 promotes cell growth and survival in colorectal cancer. Int J Clin Exp Pathol. 2014;7:6006–14.25337245
30. Hassanein M Hoeksema MD Shiota M Qian J Harris BK Chen H Clark JE Alborn WE Eisenberg R Massion PP SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival Clin Cancer Res Off J Am Assoc Cancer Res 2013 19 560 570 10.1158/1078-0432.CCR-12-2334
Hassanein M, Hoeksema MD, Shiota M, Qian J, Harris BK, Chen H, Clark JE, Alborn WE, Eisenberg R, Massion PP. SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Clin Cancer Res Off J Am Assoc Cancer Res. 2013;19:560–70. 10.1158/1078-0432.CCR-12-2334.10.1158/1078-0432.CCR-12-2334
31. Wang Q Hardie R-A Hoy AJ van Geldermalsen M Gao D Fazli L Sadowski MC Balaban S Schreuder M Nagarajah R Wong JJ-L Metierre C Pinello N Otte NJ Lehman ML Gleave M Nelson CC Bailey CG Ritchie W Rasko JEJ Holst J Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development J Pathol 2015 236 278 289 10.1002/path.4518 25693838
Wang Q, Hardie R-A, Hoy AJ, van Geldermalsen M, Gao D, Fazli L, Sadowski MC, Balaban S, Schreuder M, Nagarajah R, Wong JJ-L, Metierre C, Pinello N, Otte NJ, Lehman ML, Gleave M, Nelson CC, Bailey CG, Ritchie W, Rasko JEJ, Holst J. Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. J Pathol. 2015;236:278–89. 10.1002/path.4518.25693838 10.1002/path.4518
32. Nikkuni O Kaira K Toyoda M Shino M Sakakura K Takahashi K Tominaga H Oriuchi N Suzuki M Iijima M Asao T Nishiyama M Nagamori S Kanai Y Oyama T Chikamatsu K Expression of amino acid transporters (LAT1 and ASCT2) in patients with stage III/IV laryngeal squamous cell carcinoma Pathol Oncol Res POR 2015 21 1175 1181 10.1007/s12253-015-9954-3 26024742
Nikkuni O, Kaira K, Toyoda M, Shino M, Sakakura K, Takahashi K, Tominaga H, Oriuchi N, Suzuki M, Iijima M, Asao T, Nishiyama M, Nagamori S, Kanai Y, Oyama T, Chikamatsu K. Expression of amino acid transporters (LAT1 and ASCT2) in patients with stage III/IV laryngeal squamous cell carcinoma. Pathol Oncol Res POR. 2015;21:1175–81. 10.1007/s12253-015-9954-3.26024742 10.1007/s12253-015-9954-3
33. Honjo H Kaira K Miyazaki T Yokobori T Kanai Y Nagamori S Oyama T Asao T Kuwano H Clinicopathological significance of LAT1 and ASCT2 in patients with surgically resected esophageal squamous cell carcinoma J Surg Oncol 2016 113 381 389 10.1002/jso.24160 26936531
Honjo H, Kaira K, Miyazaki T, Yokobori T, Kanai Y, Nagamori S, Oyama T, Asao T, Kuwano H. Clinicopathological significance of LAT1 and ASCT2 in patients with surgically resected esophageal squamous cell carcinoma. J Surg Oncol. 2016;113:381–9. 10.1002/jso.24160.26936531 10.1002/jso.24160
34. Ren P Yue M Xiao D Xiu R Gan L Liu H Qing G ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation J Pathol 2015 235 90 100 10.1002/path.4429 25142020
Ren P, Yue M, Xiao D, Xiu R, Gan L, Liu H, Qing G. ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation. J Pathol. 2015;235:90–100. 10.1002/path.4429.25142020 10.1002/path.4429
35. Ye J Huang Q Xu J Huang J Wang J Zhong W Chen W Lin X Lin X Targeting of glutamine transporter ASCT2 and glutamine synthetase suppresses gastric cancer cell growth J Cancer Res Clin Oncol 2018 144 821 833 10.1007/s00432-018-2605-9 29435734
Ye J, Huang Q, Xu J, Huang J, Wang J, Zhong W, Chen W, Lin X, Lin X. Targeting of glutamine transporter ASCT2 and glutamine synthetase suppresses gastric cancer cell growth. J Cancer Res Clin Oncol. 2018;144:821–33. 10.1007/s00432-018-2605-9.29435734 10.1007/s00432-018-2605-9
36. Wang W Pan H Ren F Chen H Ren P Targeting ASCT2-mediated glutamine metabolism inhibits proliferation and promotes apoptosis of pancreatic cancer cells Biosci Rep 2022 42 BSR20212171 10.1042/BSR20212171 35237783
Wang W, Pan H, Ren F, Chen H, Ren P. Targeting ASCT2-mediated glutamine metabolism inhibits proliferation and promotes apoptosis of pancreatic cancer cells. Biosci Rep. 2022;42:BSR20212171. 10.1042/BSR20212171.35237783 10.1042/BSR20212171
37. Dunphy MPS Harding JJ Venneti S Zhang H Burnazi EM Bromberg J Omuro AM Hsieh JJ Mellinghoff IK Staton K Pressl C Beattie BJ Zanzonico PB Gerecitano JF Kelsen DP Weber W Lyashchenko SK Kung HF Lewis JS In vivo PET assay of tumor glutamine flux and metabolism: in-human trial of 18F-(2S,4R)-4-fluoroglutamine Radiology 2018 287 667 675 10.1148/radiol.2017162610 29388903
Dunphy MPS, Harding JJ, Venneti S, Zhang H, Burnazi EM, Bromberg J, Omuro AM, Hsieh JJ, Mellinghoff IK, Staton K, Pressl C, Beattie BJ, Zanzonico PB, Gerecitano JF, Kelsen DP, Weber W, Lyashchenko SK, Kung HF, Lewis JS. In vivo PET assay of tumor glutamine flux and metabolism: in-human trial of 18F-(2S,4R)-4-fluoroglutamine. Radiology. 2018;287:667–75. 10.1148/radiol.2017162610.29388903 10.1148/radiol.2017162610
38. van Geldermalsen M Wang Q Nagarajah R Marshall AD Thoeng A Gao D Ritchie W Feng Y Bailey CG Deng N Harvey K Beith JM Selinger CI O’Toole SA Rasko JEJ Holst J ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer Oncogene 2016 35 3201 3208 10.1038/onc.2015.381 26455325
van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey CG, Deng N, Harvey K, Beith JM, Selinger CI, O’Toole SA, Rasko JEJ, Holst J. ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene. 2016;35:3201–8. 10.1038/onc.2015.381.26455325 10.1038/onc.2015.381
39. Döhner H Weisdorf DJ Bloomfield CD Acute myeloid leukemia N Engl J Med 2015 373 1136 1152 10.1056/NEJMra1406184 26376137
Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52. 10.1056/NEJMra1406184.26376137 10.1056/NEJMra1406184
40. Panuzzo C Jovanovski A Pergolizzi B Pironi L Stanga S Fava C Cilloni D Mitochondria: a galaxy in the hematopoietic and leukemic stem cell universe Int J Mol Sci 2020 21 3928 10.3390/ijms21113928 32486249
Panuzzo C, Jovanovski A, Pergolizzi B, Pironi L, Stanga S, Fava C, Cilloni D. Mitochondria: a galaxy in the hematopoietic and leukemic stem cell universe. Int J Mol Sci. 2020;21:3928. 10.3390/ijms21113928.32486249 10.3390/ijms21113928
41. Sánchez-Mendoza SE Rego EM Targeting the mitochondria in acute myeloid leukemia Appl Cancer Res 2017 37 22 10.1186/s41241-017-0022-z
Sánchez-Mendoza SE, Rego EM. Targeting the mitochondria in acute myeloid leukemia. Appl Cancer Res. 2017;37:22. 10.1186/s41241-017-0022-z.10.1186/s41241-017-0022-z
42. Ward PS Patel J Wise DR Abdel-Wahab O Bennett BD Coller HA Cross JR Fantin VR Hedvat CV Perl AE Rabinowitz JD Carroll M Su SM Sharp KA Levine RL Thompson CB The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate Cancer Cell 2010 17 225 234 10.1016/j.ccr.2010.01.020 20171147
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzymatic activity that converts α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34. 10.1016/j.ccr.2010.01.020.20171147 10.1016/j.ccr.2010.01.020
43. DeBerardinis RJ Mancuso A Daikhin E Nissim I Yudkoff M Wehrli S Thompson CB Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis Proc Natl Acad Sci USA 2007 104 19345 19350 10.1073/pnas.0709747104 18032601
DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA. 2007;104:19345–50. 10.1073/pnas.0709747104.18032601 10.1073/pnas.0709747104
44. Wang Y Zhang L Chen W-L Wang J-H Li N Li J-M Mi J-Q Zhang W-N Li Y Wu S-F Jin J Wang Y-G Huang H Chen Z Chen S-J Tang H Rapid diagnosis and prognosis of de novo acute myeloid leukemia by serum metabonomic analysis J Proteome Res 2013 12 4393 4401 10.1021/pr400403p 23998518
Wang Y, Zhang L, Chen W-L, Wang J-H, Li N, Li J-M, Mi J-Q, Zhang W-N, Li Y, Wu S-F, Jin J, Wang Y-G, Huang H, Chen Z, Chen S-J, Tang H. Rapid diagnosis and prognosis of de novo acute myeloid leukemia by serum metabonomic analysis. J Proteome Res. 2013;12:4393–401. 10.1021/pr400403p.23998518 10.1021/pr400403p
45. Rudman D Vogler WR Howard CH Gerron GG Observations on the plasma amino acids of patients with acute leukemia Cancer Res 1971 31 1159 1165 5285976
Rudman D, Vogler WR, Howard CH, Gerron GG. Observations on the plasma amino acids of patients with acute leukemia. Cancer Res. 1971;31:1159–65.5285976
46. Wang D Tan G Wang H Chen P Hao J Wang Y Identification of novel serum biomarker for the detection of acute myeloid leukemia based on liquid chromatography-mass spectrometry J Pharm Biomed Anal 2019 166 357 363 10.1016/j.jpba.2019.01.022 30690249
Wang D, Tan G, Wang H, Chen P, Hao J, Wang Y. Identification of novel serum biomarker for the detection of acute myeloid leukemia based on liquid chromatography-mass spectrometry. J Pharm Biomed Anal. 2019;166:357–63. 10.1016/j.jpba.2019.01.022.30690249 10.1016/j.jpba.2019.01.022
47. Willems L Jacque N Jacquel A Neveux N Maciel TT Lambert M Schmitt A Poulain L Green AS Uzunov M Kosmider O Radford-Weiss I Moura IC Auberger P Ifrah N Bardet V Chapuis N Lacombe C Mayeux P Tamburini J Bouscary D Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia Blood 2013 122 3521 3532 10.1182/blood-2013-03-493163 24014241
Willems L, Jacque N, Jacquel A, Neveux N, Maciel TT, Lambert M, Schmitt A, Poulain L, Green AS, Uzunov M, Kosmider O, Radford-Weiss I, Moura IC, Auberger P, Ifrah N, Bardet V, Chapuis N, Lacombe C, Mayeux P, Tamburini J, Bouscary D. Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Blood. 2013;122:3521–32. 10.1182/blood-2013-03-493163.24014241 10.1182/blood-2013-03-493163
48. Matre P Velez J Jacamo R Qi Y Su X Cai T Chan SM Lodi A Sweeney SR Ma H Davis RE Baran N Haferlach T Su X Flores ER Gonzalez D Konoplev S Samudio I DiNardo C Majeti R Schimmer AD Li W Wang T Tiziani S Konopleva M Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes Oncotarget 2016 7 79722 79735 10.18632/oncotarget.12944 27806325
Matre P, Velez J, Jacamo R, Qi Y, Su X, Cai T, Chan SM, Lodi A, Sweeney SR, Ma H, Davis RE, Baran N, Haferlach T, Su X, Flores ER, Gonzalez D, Konoplev S, Samudio I, DiNardo C, Majeti R, Schimmer AD, Li W, Wang T, Tiziani S, Konopleva M. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget. 2016;7:79722–35. 10.18632/oncotarget.12944.27806325 10.18632/oncotarget.12944
49. Emadi A Jun SA Tsukamoto T Fathi AT Minden MD Dang CV Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations Exp Hematol 2014 42 247 251 10.1016/j.exphem.2013.12.001 24333121
Emadi A, Jun SA, Tsukamoto T, Fathi AT, Minden MD, Dang CV. Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. Exp Hematol. 2014;42:247–51. 10.1016/j.exphem.2013.12.001.24333121 10.1016/j.exphem.2013.12.001
50. Basak NP Banerjee S Mitochondrial dependency in progression of acute myeloid leukemia Mitochondrion 2015 21 41 48 10.1016/j.mito.2015.01.006 25640960
Basak NP, Banerjee S. Mitochondrial dependency in progression of acute myeloid leukemia. Mitochondrion. 2015;21:41–8. 10.1016/j.mito.2015.01.006.25640960 10.1016/j.mito.2015.01.006
51. Wagner A Kosnacova H Chovanec M Jurkovicova D Mitochondrial genetic and epigenetic regulations in cancer: therapeutic potential Int J Mol Sci 2022 23 7897 10.3390/ijms23147897 35887244
Wagner A, Kosnacova H, Chovanec M, Jurkovicova D. Mitochondrial genetic and epigenetic regulations in cancer: therapeutic potential. Int J Mol Sci. 2022;23:7897. 10.3390/ijms23147897.35887244 10.3390/ijms23147897
52. Sharma ND Keewan E Matlawska-Wasowska K Metabolic reprogramming and cell adhesion in acute leukemia adaptation to the CNS niche Front Cell Dev Biol 2021 9 767510 10.3389/fcell.2021.767510 34957100
Sharma ND, Keewan E, Matlawska-Wasowska K. Metabolic reprogramming and cell adhesion in acute leukemia adaptation to the CNS niche. Front Cell Dev Biol. 2021;9: 767510. 10.3389/fcell.2021.767510.34957100 10.3389/fcell.2021.767510
53. Weng H Huang F Yu Z Chen Z Prince E Kang Y Zhou K Li W Hu J Fu C Aziz T Li H Li J Yang Y Han L Zhang S Ma Y Sun M Wu H Zhang Z Wunderlich M Robinson S Braas D Hoeve JT Zhang B Marcucci G Mulloy JC Zhou K Tao H-F Deng X Horne D Wei M Huang H Chen J The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia Cancer Cell 2022 40 1566 1582.e10 10.1016/j.ccell.2022.10.004 36306790
Weng H, Huang F, Yu Z, Chen Z, Prince E, Kang Y, Zhou K, Li W, Hu J, Fu C, Aziz T, Li H, Li J, Yang Y, Han L, Zhang S, Ma Y, Sun M, Wu H, Zhang Z, Wunderlich M, Robinson S, Braas D, Hoeve JT, Zhang B, Marcucci G, Mulloy JC, Zhou K, Tao H-F, Deng X, Horne D, Wei M, Huang H, Chen J. The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia. Cancer Cell. 2022;40:1566-1582.e10. 10.1016/j.ccell.2022.10.004.36306790 10.1016/j.ccell.2022.10.004
54. Song M Kim S-H Im CY Hwang H-J Recent development of small molecule glutaminase inhibitors Curr Top Med Chem 2018 18 432 443 10.2174/1568026618666180525100830 29793408
Song M, Kim S-H, Im CY, Hwang H-J. Recent development of small molecule glutaminase inhibitors. Curr Top Med Chem. 2018;18:432–43. 10.2174/1568026618666180525100830.29793408 10.2174/1568026618666180525100830
55. Jacque N Ronchetti AM Larrue C Meunier G Birsen R Willems L Saland E Decroocq J Maciel TT Lambert M Poulain L Hospital MA Sujobert P Joseph L Chapuis N Lacombe C Moura IC Demo S Sarry JE Recher C Mayeux P Tamburini J Bouscary D Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition Blood 2015 126 1346 1356 10.1182/blood-2015-01-621870 26186940
Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, Saland E, Decroocq J, Maciel TT, Lambert M, Poulain L, Hospital MA, Sujobert P, Joseph L, Chapuis N, Lacombe C, Moura IC, Demo S, Sarry JE, Recher C, Mayeux P, Tamburini J, Bouscary D. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood. 2015;126:1346–56. 10.1182/blood-2015-01-621870.26186940 10.1182/blood-2015-01-621870
56. Mao H Wen Y Yu Y Li H Wang J Sun B Bioinspired nanocatalytic tumor therapy by simultaneous reactive oxygen species generation enhancement and glutamine pathway-mediated glutathione depletion J Mater Chem B 2022 11 131 143 10.1039/d2tb02194c 36484247
Mao H, Wen Y, Yu Y, Li H, Wang J, Sun B. Bioinspired nanocatalytic tumor therapy by simultaneous reactive oxygen species generation enhancement and glutamine pathway-mediated glutathione depletion. J Mater Chem B. 2022;11:131–43. 10.1039/d2tb02194c.36484247 10.1039/d2tb02194c
57. Boysen G Jamshidi-Parsian A Davis MA Siegel ER Kore RA Dings RPM Griffin RJ Glutaminase inhibitor CB-839 increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice Int J Radiat Biol 2019 95 436 442 10.1080/09553002.2018.1558299 30557074
Boysen G, Jamshidi-Parsian A, Davis MA, Siegel ER, Kore RA, Dings RPM, Griffin RJ. Glutaminase inhibitor CB-839 increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice. Int J Radiat Biol. 2019;95:436–42. 10.1080/09553002.2018.1558299.30557074 10.1080/09553002.2018.1558299
58. Romo-González M Ijurko C Hernández-Hernández Á Reactive oxygen species and metabolism in leukemia: a dangerous liaison Front Immunol 2022 13 889875 10.3389/fimmu.2022.889875 35757686
Romo-González M, Ijurko C, Hernández-Hernández Á. Reactive oxygen species and metabolism in leukemia: a dangerous liaison. Front Immunol. 2022;13: 889875. 10.3389/fimmu.2022.889875.35757686 10.3389/fimmu.2022.889875
59. Chen Y-F Liu H Luo X-J Zhao Z Zou Z-Y Li J Lin X-J Liang Y The roles of reactive oxygen species (ROS) and autophagy in the survival and death of leukemia cells Crit Rev Oncol Hematol 2017 112 21 30 10.1016/j.critrevonc.2017.02.004 28325262
Chen Y-F, Liu H, Luo X-J, Zhao Z, Zou Z-Y, Li J, Lin X-J, Liang Y. The roles of reactive oxygen species (ROS) and autophagy in the survival and death of leukemia cells. Crit Rev Oncol Hematol. 2017;112:21–30. 10.1016/j.critrevonc.2017.02.004.28325262 10.1016/j.critrevonc.2017.02.004
60. Kreitz J Schönfeld C Seibert M Stolp V Alshamleh I Oellerich T Steffen B Schwalbe H Schnütgen F Kurrle N Serve H Metabolic plasticity of acute myeloid leukemia Cells 2019 8 805 10.3390/cells8080805 31370337
Kreitz J, Schönfeld C, Seibert M, Stolp V, Alshamleh I, Oellerich T, Steffen B, Schwalbe H, Schnütgen F, Kurrle N, Serve H. Metabolic plasticity of acute myeloid leukemia. Cells. 2019;8:805. 10.3390/cells8080805.31370337 10.3390/cells8080805
61. Gregory MA Nemkov T Reisz JA Zaberezhnyy V Hansen KC D’Alessandro A DeGregori J Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia Exp Hematol 2018 58 52 58 10.1016/j.exphem.2017.09.007 28947392
Gregory MA, Nemkov T, Reisz JA, Zaberezhnyy V, Hansen KC, D’Alessandro A, DeGregori J. Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia. Exp Hematol. 2018;58:52–8. 10.1016/j.exphem.2017.09.007.28947392 10.1016/j.exphem.2017.09.007
62. Khamari R Degand C Fovez Q Trinh A Chomy A Laine W Dekiouk S Ghesquiere B Quesnel B Marchetti P Manier S Kluza PJ Key role of glutamine metabolism in persistence of leukemic cells upon exposition to FLT3 tyrosine kinase inhibitors Exp Hematol 2024 10.1016/j.exphem.2024.104253 38879112
Khamari R, Degand C, Fovez Q, Trinh A, Chomy A, Laine W, Dekiouk S, Ghesquiere B, Quesnel B, Marchetti P, Manier S, Kluza PJ. Key role of glutamine metabolism in persistence of leukemic cells upon exposition to FLT3 tyrosine kinase inhibitors. Exp Hematol. 2024. 10.1016/j.exphem.2024.104253.38879112 10.1016/j.exphem.2024.104253
63. Gregory MA D’Alessandro A Alvarez-Calderon F Kim J Nemkov T Adane B Rozhok AI Kumar A Kumar V Pollyea DA Wempe MF Jordan CT Serkova NJ Tan AC Hansen KC DeGregori J ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia Proc Natl Acad Sci U S A 2016 113 E6669 E6678 10.1073/pnas.1603876113 27791036
Gregory MA, D’Alessandro A, Alvarez-Calderon F, Kim J, Nemkov T, Adane B, Rozhok AI, Kumar A, Kumar V, Pollyea DA, Wempe MF, Jordan CT, Serkova NJ, Tan AC, Hansen KC, DeGregori J. ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia. Proc Natl Acad Sci U S A. 2016;113:E6669–78. 10.1073/pnas.1603876113.27791036 10.1073/pnas.1603876113
64. Scheid C Hermann K Kremer G Holsing A Heck G Fuchs M Waldschmidt D Herrmann H-J Söhngen D Diehl V Schwenk A Randomized, double-blind, controlled study of glycyl-glutamine-dipeptide in the parenteral nutrition of patients with acute leukemia undergoing intensive chemotherapy Nutr Burbank Los Angel Cty Calif 2004 20 249 254 10.1016/j.nut.2003.11.018
Scheid C, Hermann K, Kremer G, Holsing A, Heck G, Fuchs M, Waldschmidt D, Herrmann H-J, Söhngen D, Diehl V, Schwenk A. Randomized, double-blind, controlled study of glycyl-glutamine-dipeptide in the parenteral nutrition of patients with acute leukemia undergoing intensive chemotherapy. Nutr Burbank Los Angel Cty Calif. 2004;20:249–54. 10.1016/j.nut.2003.11.018.10.1016/j.nut.2003.11.018
65. Timofeeva N Ayres ML Baran N Santiago-O’Farrill JM Bildik G Lu Z Konopleva M Gandhi V Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia Front Oncol 2023 13 1161254 10.3389/fonc.2023.1161254 37228498
Timofeeva N, Ayres ML, Baran N, Santiago-O’Farrill JM, Bildik G, Lu Z, Konopleva M, Gandhi V. Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia. Front Oncol. 2023;13:1161254. 10.3389/fonc.2023.1161254.37228498 10.3389/fonc.2023.1161254
66. Galicia-Vázquez G Smith S Aloyz R Del11q-positive CLL lymphocytes exhibit altered glutamine metabolism and differential response to GLS1 and glucose metabolism inhibition Blood Cancer J 2018 8 13 10.1038/s41408-017-0039-2 29367649
Galicia-Vázquez G, Smith S, Aloyz R. Del11q-positive CLL lymphocytes exhibit altered glutamine metabolism and differential response to GLS1 and glucose metabolism inhibition. Blood Cancer J. 2018;8:13. 10.1038/s41408-017-0039-2.29367649 10.1038/s41408-017-0039-2
67. Jitschin R Hofmann AD Bruns H Giessl A Bricks J Berger J Saul D Eckart MJ Mackensen A Mougiakakos D Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia Blood 2014 123 2663 2672 10.1182/blood-2013-10-532200 24553174
Jitschin R, Hofmann AD, Bruns H, Giessl A, Bricks J, Berger J, Saul D, Eckart MJ, Mackensen A, Mougiakakos D. Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia. Blood. 2014;123:2663–72. 10.1182/blood-2013-10-532200.24553174 10.1182/blood-2013-10-532200
68. Deaglio S Glutamine and CLL: ready for prime time? Blood 2022 140 528 529 10.1182/blood.2022016696 35951344
Deaglio S. Glutamine and CLL: ready for prime time? Blood. 2022;140:528–9. 10.1182/blood.2022016696.35951344 10.1182/blood.2022016696
69. Terwilliger T Abdul-Hay M Acute lymphoblastic leukemia: a comprehensive review and 2017 update Blood Cancer J 2017 7 e577 10.1038/bcj.2017.53 28665419
Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7: e577. 10.1038/bcj.2017.53.28665419 10.1038/bcj.2017.53
70. Ward E DeSantis C Robbins A Kohler B Jemal A Childhood and adolescent cancer statistics, 2014 CA Cancer J Clin 2014 64 83 103 10.3322/caac.21219 24488779
Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. 2014;64:83–103. 10.3322/caac.21219.24488779 10.3322/caac.21219
71. Avramis VI Tiwari PN Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia Int J Nanomed 2006 1 241 254
Avramis VI, Tiwari PN. Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia. Int J Nanomed. 2006;1:241–54.
72. Beard ME Crowther D Galton DA Guyer RJ Fairley GH Kay HE Knapton PJ Malpas JS Scott RB L-asparaginase in treatment of acute leukaemia and lymphosarcoma Br Med J 1970 1 191 195 10.1136/bmj.1.5690.191 4904933
Beard ME, Crowther D, Galton DA, Guyer RJ, Fairley GH, Kay HE, Knapton PJ, Malpas JS, Scott RB. L-asparaginase in treatment of acute leukaemia and lymphosarcoma. Br Med J. 1970;1:191–5. 10.1136/bmj.1.5690.191.4904933 10.1136/bmj.1.5690.191
73. Patil S Coutsouvelis J Spencer A Asparaginase in the management of adult acute lymphoblastic leukaemia: is it used appropriately? Cancer Treat Rev 2011 37 202 207 10.1016/j.ctrv.2010.08.002 20822851
Patil S, Coutsouvelis J, Spencer A. Asparaginase in the management of adult acute lymphoblastic leukaemia: is it used appropriately? Cancer Treat Rev. 2011;37:202–7. 10.1016/j.ctrv.2010.08.002.20822851 10.1016/j.ctrv.2010.08.002
74. Nguyen TL Nokin M-J Terés S Tomé M Bodineau C Galmar O Pasquet J-M Rousseau B van Liempd S Falcon-Perez JM Richard E Muzotte E Rezvani H-R Priault M Bouchecareilh M Redonnet-Vernhet I Calvo J Uzan B Pflumio F Fuentes P Toribio ML Khatib A-M Soubeyran P Murdoch PDS Durán RV Downregulation of glutamine synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia Mol Oncol 2021 15 1412 1431 10.1002/1878-0261.12877 33314742
Nguyen TL, Nokin M-J, Terés S, Tomé M, Bodineau C, Galmar O, Pasquet J-M, Rousseau B, van Liempd S, Falcon-Perez JM, Richard E, Muzotte E, Rezvani H-R, Priault M, Bouchecareilh M, Redonnet-Vernhet I, Calvo J, Uzan B, Pflumio F, Fuentes P, Toribio ML, Khatib A-M, Soubeyran P, Murdoch PDS, Durán RV. Downregulation of glutamine synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia. Mol Oncol. 2021;15:1412–31. 10.1002/1878-0261.12877.33314742 10.1002/1878-0261.12877
75. Ehsanipour EA Sheng X Behan JW Wang X Butturini A Avramis VI Mittelman SD Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine Cancer Res 2013 73 2998 3006 10.1158/0008-5472.CAN-12-4402 23585457
Ehsanipour EA, Sheng X, Behan JW, Wang X, Butturini A, Avramis VI, Mittelman SD. Adipocytes cause leukemia cell resistance to L-asparaginase via release of glutamine. Cancer Res. 2013;73:2998–3006. 10.1158/0008-5472.CAN-12-4402.23585457 10.1158/0008-5472.CAN-12-4402
76. Tabe Y Lorenzi PL Konopleva M Amino acid metabolism in hematologic malignancies and the era of targeted therapy Blood 2019 134 1014 1023 10.1182/blood.2019001034 31416801
Tabe Y, Lorenzi PL, Konopleva M. Amino acid metabolism in hematologic malignancies and the era of targeted therapy. Blood. 2019;134:1014–23. 10.1182/blood.2019001034.31416801 10.1182/blood.2019001034
77. Cory JG Cory AH Critical roles of glutamine as nitrogen donors in purine and pyrimidine nucleotide synthesis: asparaginase treatment in childhood acute lymphoblastic leukemia Vivo Athens Greece 2006 20 587 589
Cory JG, Cory AH. Critical roles of glutamine as nitrogen donors in purine and pyrimidine nucleotide synthesis: asparaginase treatment in childhood acute lymphoblastic leukemia. Vivo Athens Greece. 2006;20:587–9.
78. Han Y Zhang F Wang J Zhu Y Dai J Bu Y Yang Q Xiao Y Sun X Application of Glutamine-enriched nutrition therapy in childhood acute lymphoblastic leukemia Nutr J 2016 15 65 10.1186/s12937-016-0187-4 27401338
Han Y, Zhang F, Wang J, Zhu Y, Dai J, Bu Y, Yang Q, Xiao Y, Sun X. Application of Glutamine-enriched nutrition therapy in childhood acute lymphoblastic leukemia. Nutr J. 2016;15:65. 10.1186/s12937-016-0187-4.27401338 10.1186/s12937-016-0187-4
79. Mullighan CG Phillips LA Su X Ma J Miller CB Shurtleff SA Downing JR Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia Science 2008 322 1377 1380 10.1126/science.1164266 19039135
Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA, Downing JR. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. 2008;322:1377–80. 10.1126/science.1164266.19039135 10.1126/science.1164266
80. Stäubert C Bhuiyan H Lindahl A Broom OJ Zhu Y Islam S Linnarsson S Lehtiö J Nordström A Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine J Biol Chem 2015 290 8348 8359 10.1074/jbc.M114.618769 25697355
Stäubert C, Bhuiyan H, Lindahl A, Broom OJ, Zhu Y, Islam S, Linnarsson S, Lehtiö J, Nordström A. Rewired metabolism in drug-resistant leukemia cells: a metabolic switch hallmarked by reduced dependence on exogenous glutamine. J Biol Chem. 2015;290:8348–59. 10.1074/jbc.M114.618769.25697355 10.1074/jbc.M114.618769
81. Mannan A Germon ZP Chamberlain J Sillar JR Nixon B Dun MD Reactive oxygen species in acute lymphoblastic leukaemia: reducing radicals to refine responses Antioxid Basel Switz 2021 10 1616 10.3390/antiox10101616
Mannan A, Germon ZP, Chamberlain J, Sillar JR, Nixon B, Dun MD. Reactive oxygen species in acute lymphoblastic leukaemia: reducing radicals to refine responses. Antioxid Basel Switz. 2021;10:1616. 10.3390/antiox10101616.10.3390/antiox10101616
82. Birben E Sahiner UM Sackesen C Erzurum S Kalayci O Oxidative stress and antioxidant defense World Allergy Organ J 2012 5 9 19 10.1097/WOX.0b013e3182439613 23268465
Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J. 2012;5:9–19. 10.1097/WOX.0b013e3182439613.23268465 10.1097/WOX.0b013e3182439613
83. Herranz D Ambesi-Impiombato A Sudderth J Sánchez-Martín M Belver L Tosello V Xu L Wendorff AA Castillo M Haydu JE Márquez J Matés JM Kung AL Rayport S Cordon-Cardo C DeBerardinis RJ Ferrando AA Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in acute lymphoblastic leukemia Nat Med 2015 21 1182 1189 10.1038/nm.3955 26390244
Herranz D, Ambesi-Impiombato A, Sudderth J, Sánchez-Martín M, Belver L, Tosello V, Xu L, Wendorff AA, Castillo M, Haydu JE, Márquez J, Matés JM, Kung AL, Rayport S, Cordon-Cardo C, DeBerardinis RJ, Ferrando AA. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in acute lymphoblastic leukemia. Nat Med. 2015;21:1182–9. 10.1038/nm.3955.26390244 10.1038/nm.3955
84. Sancerni T Renoult O Luby A Caradeuc C Lenoir V Croyal M Ransy C Aguilar E Postic C Bertho G Dentin R Prip-Buus C Pecqueur C Alves-Guerra M-C UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling Front Immunol 2022 13 960226 10.3389/fimmu.2022.960226 36275699
Sancerni T, Renoult O, Luby A, Caradeuc C, Lenoir V, Croyal M, Ransy C, Aguilar E, Postic C, Bertho G, Dentin R, Prip-Buus C, Pecqueur C, Alves-Guerra M-C. UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling. Front Immunol. 2022;13: 960226. 10.3389/fimmu.2022.960226.36275699 10.3389/fimmu.2022.960226
85. Raho S Capobianco L Malivindi R Vozza A Piazzolla C De Leonardis F Gorgoglione R Scarcia P Pezzuto F Agrimi G Barile SN Pisano I Reshkin SJ Greco MR Cardone RA Rago V Li Y Marobbio CMT Sommergruber W Riley CL Lasorsa FM Mills E Vegliante MC De Benedetto GE Fratantonio D Palmieri L Dolce V Fiermonte G KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth Nat Metab 2020 2 1373 1381 10.1038/s42255-020-00315-1 33230296
Raho S, Capobianco L, Malivindi R, Vozza A, Piazzolla C, De Leonardis F, Gorgoglione R, Scarcia P, Pezzuto F, Agrimi G, Barile SN, Pisano I, Reshkin SJ, Greco MR, Cardone RA, Rago V, Li Y, Marobbio CMT, Sommergruber W, Riley CL, Lasorsa FM, Mills E, Vegliante MC, De Benedetto GE, Fratantonio D, Palmieri L, Dolce V, Fiermonte G. KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth. Nat Metab. 2020;2:1373–81. 10.1038/s42255-020-00315-1.33230296 10.1038/s42255-020-00315-1
86. Liu Y Wan Y Jiang Y Zhang L Cheng W GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment Biochim Biophys Acta Rev Cancer 2023 1878 188890 10.1016/j.bbcan.2023.188890 37001616
Liu Y, Wan Y, Jiang Y, Zhang L, Cheng W. GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment. Biochim Biophys Acta Rev Cancer. 2023;1878: 188890. 10.1016/j.bbcan.2023.188890.37001616 10.1016/j.bbcan.2023.188890
87. Jiang X Stockwell BR Conrad M Ferroptosis: mechanisms, biology and role in disease Nat Rev Mol Cell Biol 2021 22 266 282 10.1038/s41580-020-00324-8 33495651
Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–82. 10.1038/s41580-020-00324-8.33495651 10.1038/s41580-020-00324-8
88. Rochette L Dogon G Rigal E Zeller M Cottin Y Vergely C Lipid Peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis Int J Mol Sci 2022 24 449 10.3390/ijms24010449 36613888
Rochette L, Dogon G, Rigal E, Zeller M, Cottin Y, Vergely C. Lipid Peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis. Int J Mol Sci. 2022;24:449. 10.3390/ijms24010449.36613888 10.3390/ijms24010449
89. Chen K Albano A Ho A Keaney JF Activation of p53 by oxidative stress involves platelet-derived growth factor-beta receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation J Biol Chem 2003 278 39527 39533 10.1074/jbc.M304423200 12890678
Chen K, Albano A, Ho A, Keaney JF. Activation of p53 by oxidative stress involves platelet-derived growth factor-beta receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation. J Biol Chem. 2003;278:39527–33. 10.1074/jbc.M304423200.12890678 10.1074/jbc.M304423200
90. Xu T Ding W Ji X Ao X Liu Y Yu W Wang J Molecular mechanisms of ferroptosis and its role in cancer therapy J Cell Mol Med 2019 23 4900 4912 10.1111/jcmm.14511 31232522
Xu T, Ding W, Ji X, Ao X, Liu Y, Yu W, Wang J. Molecular mechanisms of ferroptosis and its role in cancer therapy. J Cell Mol Med. 2019;23:4900–12. 10.1111/jcmm.14511.31232522 10.1111/jcmm.14511
91. Yan H-F Zou T Tuo Q-Z Xu S Li H Belaidi AA Lei P Ferroptosis: mechanisms and links with diseases Signal Transduct Target Ther 2021 6 49 10.1038/s41392-020-00428-9 33536413
Yan H-F, Zou T, Tuo Q-Z, Xu S, Li H, Belaidi AA, Lei P. Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther. 2021;6:49. 10.1038/s41392-020-00428-9.33536413 10.1038/s41392-020-00428-9
92. Gao M Monian P Quadri N Ramasamy R Jiang X Glutaminolysis and transferrin regulate ferroptosis Mol Cell 2015 59 298 308 10.1016/j.molcel.2015.06.011 26166707
Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59:298–308. 10.1016/j.molcel.2015.06.011.26166707 10.1016/j.molcel.2015.06.011
93. Weinberg F Hamanaka R Wheaton WW Weinberg S Joseph J Lopez M Kalyanaraman B Mutlu GM Budinger GRS Chandel NS Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity Proc Natl Acad Sci USA 2010 107 8788 8793 10.1073/pnas.1003428107 20421486
Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GRS, Chandel NS. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA. 2010;107:8788–93. 10.1073/pnas.1003428107.20421486 10.1073/pnas.1003428107
94. Anderson NM Mucka P Kern JG Feng H The emerging role and targetability of the TCA cycle in cancer metabolism Protein Cell 2018 9 216 237 10.1007/s13238-017-0451-1 28748451
Anderson NM, Mucka P, Kern JG, Feng H. The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell. 2018;9:216–37. 10.1007/s13238-017-0451-1.28748451 10.1007/s13238-017-0451-1
95. Panieri E Santoro MM ROS homeostasis and metabolism: a dangerous liason in cancer cells Cell Death Dis 2016 7 e2253 10.1038/cddis.2016.105 27277675
Panieri E, Santoro MM. ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis. 2016;7: e2253. 10.1038/cddis.2016.105.27277675 10.1038/cddis.2016.105
96. Gao M Yi J Zhu J Minikes AM Monian P Thompson CB Jiang X Role of mitochondria in ferroptosis Mol Cell 2019 73 354 363.e3 10.1016/j.molcel.2018.10.042 30581146
Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, Jiang X. Role of mitochondria in ferroptosis. Mol Cell. 2019;73:354-363.e3. 10.1016/j.molcel.2018.10.042.30581146 10.1016/j.molcel.2018.10.042
97. Buczkowska J Szeliga M Two faces of glutaminase GLS2 in carcinogenesis Cancers 2023 15 5566 10.3390/cancers15235566 38067269
Buczkowska J, Szeliga M. Two faces of glutaminase GLS2 in carcinogenesis. Cancers. 2023;15:5566. 10.3390/cancers15235566.38067269 10.3390/cancers15235566
98. Suzuki S Venkatesh D Kanda H Nakayama A Hosokawa H Lee E Miki T Stockwell BR Yokote K Tanaka T Prives C GLS2 is a tumor suppressor and a regulator of ferroptosis in hepatocellular carcinoma Cancer Res 2022 82 3209 3222 10.1158/0008-5472.CAN-21-3914 35895807
Suzuki S, Venkatesh D, Kanda H, Nakayama A, Hosokawa H, Lee E, Miki T, Stockwell BR, Yokote K, Tanaka T, Prives C. GLS2 is a tumor suppressor and a regulator of ferroptosis in hepatocellular carcinoma. Cancer Res. 2022;82:3209–22. 10.1158/0008-5472.CAN-21-3914.35895807 10.1158/0008-5472.CAN-21-3914
99. Suzuki S Venkatesh D Tanaka T Prives C GLS2 shapes ferroptosis in hepatocellular carcinoma Oncotarget 2023 14 900 903 10.18632/oncotarget.28526 37861381
Suzuki S, Venkatesh D, Tanaka T, Prives C. GLS2 shapes ferroptosis in hepatocellular carcinoma. Oncotarget. 2023;14:900–3. 10.18632/oncotarget.28526.37861381 10.18632/oncotarget.28526
100. Durán RV Oppliger W Robitaille AM Heiserich L Skendaj R Gottlieb E Hall MN Glutaminolysis activates Rag-mTORC1 signaling Mol Cell 2012 47 349 358 10.1016/j.molcel.2012.05.043 22749528
Durán RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell. 2012;47:349–58. 10.1016/j.molcel.2012.05.043.22749528 10.1016/j.molcel.2012.05.043
101. Wang L Zhu L Wu K Chen Y Lee D-Y Gucek M Sack MN Mitochondrial general control of amino acid synthesis 5 Like 1 regulates glutaminolysis, mTORC1 activity and murine liver regeneration Hepatol Baltim Md 2020 71 643 657 10.1002/hep.30876
Wang L, Zhu L, Wu K, Chen Y, Lee D-Y, Gucek M, Sack MN. Mitochondrial general control of amino acid synthesis 5 Like 1 regulates glutaminolysis, mTORC1 activity and murine liver regeneration. Hepatol Baltim Md. 2020;71:643–57. 10.1002/hep.30876.10.1002/hep.30876
102. Zhu J Wang H Jiang X mTORC1 beyond anabolic metabolism: regulation of cell death J Cell Biol 2022 221 e202208103 10.1083/jcb.202208103 36282248
Zhu J, Wang H, Jiang X. mTORC1 beyond anabolic metabolism: regulation of cell death. J Cell Biol. 2022;221: e202208103. 10.1083/jcb.202208103.36282248 10.1083/jcb.202208103
103. Zhang Y Swanda RV Nie L Liu X Wang C Lee H Lei G Mao C Koppula P Cheng W Zhang J Xiao Z Zhuang L Fang B Chen J Qian S-B Gan B mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation Nat Commun 2021 12 1589 10.1038/s41467-021-21841-w 33707434
Zhang Y, Swanda RV, Nie L, Liu X, Wang C, Lee H, Lei G, Mao C, Koppula P, Cheng W, Zhang J, Xiao Z, Zhuang L, Fang B, Chen J, Qian S-B, Gan B. mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat Commun. 2021;12:1589. 10.1038/s41467-021-21841-w.33707434 10.1038/s41467-021-21841-w
104. Jin H Wang S Zaal EA Wang C Wu H Bosma A Jochems F Isima N Jin G Lieftink C Beijersbergen R Berkers CR Qin W Bernards R A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer Elife 2020 9 e56749 10.7554/eLife.56749 33016874
Jin H, Wang S, Zaal EA, Wang C, Wu H, Bosma A, Jochems F, Isima N, Jin G, Lieftink C, Beijersbergen R, Berkers CR, Qin W, Bernards R. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. Elife. 2020;9: e56749. 10.7554/eLife.56749.33016874 10.7554/eLife.56749
105. Li Q-Q Pan S-Y Chen Q-Y Zhou W Wang S-Q Effect of competitive antagonist of transmembrane glutamine flux V-9302 on apoptosis of acute myeloid leukemia cell lines HL-60 and KG-1 Zhongguo Shi Yan Xue Ye Xue Za Zhi 2021 29 685 689 10.19746/j.cnki.issn.1009-2137.2021.03.005 34105457
Li Q-Q, Pan S-Y, Chen Q-Y, Zhou W, Wang S-Q. Effect of competitive antagonist of transmembrane glutamine flux V-9302 on apoptosis of acute myeloid leukemia cell lines HL-60 and KG-1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021;29:685–9. 10.19746/j.cnki.issn.1009-2137.2021.03.005.34105457 10.19746/j.cnki.issn.1009-2137.2021.03.005
106. Li Y Shao H Da Z Pan J Fu B High expression of SLC38A1 predicts poor prognosis in patients with de novo acute myeloid leukemia J Cell Physiol 2019 234 20322 20328 10.1002/jcp.28632 31344987
Li Y, Shao H, Da Z, Pan J, Fu B. High expression of SLC38A1 predicts poor prognosis in patients with de novo acute myeloid leukemia. J Cell Physiol. 2019;234:20322–8. 10.1002/jcp.28632.31344987 10.1002/jcp.28632
107. Corti A Dominici S Piaggi S Belcastro E Chiu M Taurino G Pacini S Bussolati O Pompella A γ-Glutamyltransferase enzyme activity of cancer cells modulates L-γ-glutamyl-p-nitroanilide (GPNA) cytotoxicity Sci Rep 2019 9 891 10.1038/s41598-018-37385-x 30696905
Corti A, Dominici S, Piaggi S, Belcastro E, Chiu M, Taurino G, Pacini S, Bussolati O, Pompella A. γ-Glutamyltransferase enzyme activity of cancer cells modulates L-γ-glutamyl-p-nitroanilide (GPNA) cytotoxicity. Sci Rep. 2019;9:891. 10.1038/s41598-018-37385-x.30696905 10.1038/s41598-018-37385-x
108. Emadi A Law JY Strovel ET Lapidus RG Jeng LJB Lee M Blitzer MG Carter-Cooper BA Sewell D Van Der Merwe I Philip S Imran M Yu SL Li H Amrein PC Duong VH Sausville EA Baer MR Fathi AT Singh Z Bentzen SM Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia Cancer Chemother Pharmacol 2018 81 217 222 10.1007/s00280-017-3459-6 29119293
Emadi A, Law JY, Strovel ET, Lapidus RG, Jeng LJB, Lee M, Blitzer MG, Carter-Cooper BA, Sewell D, Van Der Merwe I, Philip S, Imran M, Yu SL, Li H, Amrein PC, Duong VH, Sausville EA, Baer MR, Fathi AT, Singh Z, Bentzen SM. Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia. Cancer Chemother Pharmacol. 2018;81:217–22. 10.1007/s00280-017-3459-6.29119293 10.1007/s00280-017-3459-6
109. Zavorka Thomas ME Lu X Talebi Z Jeon JY Buelow DR Gibson AA Uddin ME Brinton LT Nguyen J Collins M Lodi A Sweeney SR Campbell MJ Sweet DH Sparreboom A Lapalombella R Tiziani S Baker SD Gilteritinib inhibits glutamine uptake and utilization in FLT3-ITD-positive AML Mol Cancer Ther 2021 20 2207 2217 10.1158/1535-7163.MCT-21-0071 34518298
Zavorka Thomas ME, Lu X, Talebi Z, Jeon JY, Buelow DR, Gibson AA, Uddin ME, Brinton LT, Nguyen J, Collins M, Lodi A, Sweeney SR, Campbell MJ, Sweet DH, Sparreboom A, Lapalombella R, Tiziani S, Baker SD. Gilteritinib inhibits glutamine uptake and utilization in FLT3-ITD-positive AML. Mol Cancer Ther. 2021;20:2207–17. 10.1158/1535-7163.MCT-21-0071.34518298 10.1158/1535-7163.MCT-21-0071
110. Konopleva M DiNardo C Bhagat T Baran N Lodi A Saxena K Cai T Su X Skwarska A Guerra V Kuruvilla V Konoplev S Gordon-Mitchell S Pradhan K Aluri S Collins M Sweeney S Busquet J Rathore A Deng Q Green M Grant S Demo S Choudhary G Sahu S Agarwal B Spodek M Thiruthuvanathan V Will B Steidl U Tippett G Burger J Borthakur G Jabbour E Pemmaraju N Kadia T Kornblau S Daver N Naqvi K Short N Garcia-Manero G Tiziani S Verma A Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: clinical efficacy and correlative analyses Res Sq 2023 10.21203/rs.3.rs-2518774/v1 37162954
Konopleva M, DiNardo C, Bhagat T, Baran N, Lodi A, Saxena K, Cai T, Su X, Skwarska A, Guerra V, Kuruvilla V, Konoplev S, Gordon-Mitchell S, Pradhan K, Aluri S, Collins M, Sweeney S, Busquet J, Rathore A, Deng Q, Green M, Grant S, Demo S, Choudhary G, Sahu S, Agarwal B, Spodek M, Thiruthuvanathan V, Will B, Steidl U, Tippett G, Burger J, Borthakur G, Jabbour E, Pemmaraju N, Kadia T, Kornblau S, Daver N, Naqvi K, Short N, Garcia-Manero G, Tiziani S, Verma A. Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: clinical efficacy and correlative analyses. Res Sq. 2023. 10.21203/rs.3.rs-2518774/v1.37162954 10.21203/rs.3.rs-2518774/v1
111. Lemberg KM Vornov JJ Rais R Slusher BS We’re not “DON” yet: optimal dosing and prodrug delivery of 6-Diazo-5-oxo-L-norleucine Mol Cancer Ther 2018 17 1824 1832 10.1158/1535-7163.MCT-17-1148 30181331
Lemberg KM, Vornov JJ, Rais R, Slusher BS. We’re not “DON” yet: optimal dosing and prodrug delivery of 6-Diazo-5-oxo-L-norleucine. Mol Cancer Ther. 2018;17:1824–32. 10.1158/1535-7163.MCT-17-1148.30181331 10.1158/1535-7163.MCT-17-1148
112. Hanaford AR Alt J Rais R Wang SZ Kaur H Thorek DLJ Eberhart CG Slusher BS Martin AM Raabe EH Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma Transl Oncol 2019 12 1314 1322 10.1016/j.tranon.2019.05.013 31340195
Hanaford AR, Alt J, Rais R, Wang SZ, Kaur H, Thorek DLJ, Eberhart CG, Slusher BS, Martin AM, Raabe EH. Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma. Transl Oncol. 2019;12:1314–22. 10.1016/j.tranon.2019.05.013.31340195 10.1016/j.tranon.2019.05.013
113. Emadi A Kapadia B Bollino D Bhandary B Baer MR Niyongere S Strovel ET Kaizer H Chang E Choi EY Ma X Tighe KM Carter-Cooper B Moses BS Civin CI Mahurkar A Shetty AC Gartenhaus RB Kamangar F Lapidus RG Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia Leukemia 2021 35 1907 1924 10.1038/s41375-020-01080-6 33199836
Emadi A, Kapadia B, Bollino D, Bhandary B, Baer MR, Niyongere S, Strovel ET, Kaizer H, Chang E, Choi EY, Ma X, Tighe KM, Carter-Cooper B, Moses BS, Civin CI, Mahurkar A, Shetty AC, Gartenhaus RB, Kamangar F, Lapidus RG. Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia. Leukemia. 2021;35:1907–24. 10.1038/s41375-020-01080-6.33199836 10.1038/s41375-020-01080-6
114. Michelozzi IM Granata V De Ponti G Alberti G Tomasoni C Antolini L Gambacorti-Passerini C Gentner B Dazzi F Biondi A Coliva T Rizzari C Pievani A Serafini M Acute myeloid leukaemia niche regulates response to L-asparaginase Br J Haematol 2019 186 420 430 10.1111/bjh.15920 31044436
Michelozzi IM, Granata V, De Ponti G, Alberti G, Tomasoni C, Antolini L, Gambacorti-Passerini C, Gentner B, Dazzi F, Biondi A, Coliva T, Rizzari C, Pievani A, Serafini M. Acute myeloid leukaemia niche regulates response to L-asparaginase. Br J Haematol. 2019;186:420–30. 10.1111/bjh.15920.31044436 10.1111/bjh.15920
115. Ardalan B Arakawa M Villacorte D Jayaram H Cooney DA Effect of L-glutamine antagonists on 5-phosphoribosyl 1-pyrophosphate levels in P388 leukemia and in murine colon adenocarcinomas in vivo Biochem Pharmacol 1982 31 1509 1513 10.1016/0006-2952(82)90373-2 6178415
Ardalan B, Arakawa M, Villacorte D, Jayaram H, Cooney DA. Effect of L-glutamine antagonists on 5-phosphoribosyl 1-pyrophosphate levels in P388 leukemia and in murine colon adenocarcinomas in vivo. Biochem Pharmacol. 1982;31:1509–13. 10.1016/0006-2952(82)90373-2.6178415 10.1016/0006-2952(82)90373-2
116. Zuo F Yu J He X Single-cell metabolomics in hematopoiesis and hematological malignancies Front Oncol 2022 12 931393 10.3389/fonc.2022.931393 35912231
Zuo F, Yu J, He X. Single-cell metabolomics in hematopoiesis and hematological malignancies. Front Oncol. 2022;12: 931393. 10.3389/fonc.2022.931393.35912231 10.3389/fonc.2022.931393
117. Polet F Corbet C Pinto A Rubio LI Martherus R Bol V Drozak X Grégoire V Riant O Feron O Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth Oncotarget 2016 7 1765 1776 10.18632/oncotarget.6426 26625201
Polet F, Corbet C, Pinto A, Rubio LI, Martherus R, Bol V, Drozak X, Grégoire V, Riant O, Feron O. Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth. Oncotarget. 2016;7:1765–76. 10.18632/oncotarget.6426.26625201 10.18632/oncotarget.6426
118. Culp-Hill R D’Alessandro A Pietras EM Extinguishing the embers: targeting AML metabolism Trends Mol Med 2021 27 332 344 10.1016/j.molmed.2020.10.001 33121874
Culp-Hill R, D’Alessandro A, Pietras EM. Extinguishing the embers: targeting AML metabolism. Trends Mol Med. 2021;27:332–44. 10.1016/j.molmed.2020.10.001.33121874 10.1016/j.molmed.2020.10.001
119. Lagadinou ED Sach A Callahan K Rossi RM Neering SJ Minhajuddin M Ashton JM Pei S Grose V O’Dwyer KM Liesveld JL Brookes PS Becker MW Jordan CT BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells Cell Stem Cell 2013 12 329 341 10.1016/j.stem.2012.12.013 23333149
Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, Ashton JM, Pei S, Grose V, O’Dwyer KM, Liesveld JL, Brookes PS, Becker MW, Jordan CT. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–41. 10.1016/j.stem.2012.12.013.23333149 10.1016/j.stem.2012.12.013
120. Farge T Saland E de Toni F Aroua N Hosseini M Perry R Bosc C Sugita M Stuani L Fraisse M Scotland S Larrue C Boutzen H Féliu V Nicolau-Travers M-L Cassant-Sourdy S Broin N David M Serhan N Sarry A Tavitian S Kaoma T Vallar L Iacovoni J Linares LK Montersino C Castellano R Griessinger E Collette Y Duchamp O Barreira Y Hirsch P Palama T Gales L Delhommeau F Garmy-Susini BH Portais J-C Vergez F Selak M Danet-Desnoyers G Carroll M Récher C Sarry J-E Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism Cancer Discov 2017 7 716 735 10.1158/2159-8290.CD-16-0441 28416471
Farge T, Saland E, de Toni F, Aroua N, Hosseini M, Perry R, Bosc C, Sugita M, Stuani L, Fraisse M, Scotland S, Larrue C, Boutzen H, Féliu V, Nicolau-Travers M-L, Cassant-Sourdy S, Broin N, David M, Serhan N, Sarry A, Tavitian S, Kaoma T, Vallar L, Iacovoni J, Linares LK, Montersino C, Castellano R, Griessinger E, Collette Y, Duchamp O, Barreira Y, Hirsch P, Palama T, Gales L, Delhommeau F, Garmy-Susini BH, Portais J-C, Vergez F, Selak M, Danet-Desnoyers G, Carroll M, Récher C, Sarry J-E. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism. Cancer Discov. 2017;7:716–35. 10.1158/2159-8290.CD-16-0441.28416471 10.1158/2159-8290.CD-16-0441
121. Tabe Y Konopleva M Andreeff M Fatty acid metabolism, bone marrow adipocytes, and AML Front Oncol 2020 10 155 10.3389/fonc.2020.00155 32133293
Tabe Y, Konopleva M, Andreeff M. Fatty acid metabolism, bone marrow adipocytes, and AML. Front Oncol. 2020;10:155. 10.3389/fonc.2020.00155.32133293 10.3389/fonc.2020.00155
122. Röhrig F Schulze A The multifaceted roles of fatty acid synthesis in cancer Nat Rev Cancer 2016 16 732 749 10.1038/nrc.2016.89 27658529
Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16:732–49. 10.1038/nrc.2016.89.27658529 10.1038/nrc.2016.89
123. Beloribi-Djefaflia S Vasseur S Guillaumond F Lipid metabolic reprogramming in cancer cells Oncogenesis 2016 5 e189 10.1038/oncsis.2015.49 26807644
Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis. 2016;5: e189. 10.1038/oncsis.2015.49.26807644 10.1038/oncsis.2015.49
124. Chen Q Kirk K Shurubor YI Zhao D Arreguin AJ Shahi I Valsecchi F Primiano G Calder EL Carelli V Denton TT Beal FM Gross SS Manfredi G D’Aurelio M Rewiring of glutamine metabolism is a bioenergetic adaptation of human cells with mitochondrial DNA mutations Cell Metab 2018 27 1007 1025.e5 10.1016/j.cmet.2018.03.002 29657030
Chen Q, Kirk K, Shurubor YI, Zhao D, Arreguin AJ, Shahi I, Valsecchi F, Primiano G, Calder EL, Carelli V, Denton TT, Beal FM, Gross SS, Manfredi G, D’Aurelio M. Rewiring of glutamine metabolism is a bioenergetic adaptation of human cells with mitochondrial DNA mutations. Cell Metab. 2018;27:1007-1025.e5. 10.1016/j.cmet.2018.03.002.29657030 10.1016/j.cmet.2018.03.002
125. Polet F Martherus R Corbet C Pinto A Feron O Inhibition of glucose metabolism prevents glycosylation of the glutamine transporter ASCT2 and promotes compensatory LAT1 upregulation in leukemia cells Oncotarget 2016 7 46371 46383 10.18632/oncotarget.10131 27344174
Polet F, Martherus R, Corbet C, Pinto A, Feron O. Inhibition of glucose metabolism prevents glycosylation of the glutamine transporter ASCT2 and promotes compensatory LAT1 upregulation in leukemia cells. Oncotarget. 2016;7:46371–83. 10.18632/oncotarget.10131.27344174 10.18632/oncotarget.10131
126. van Gastel N Spinelli JB Sharda A Schajnovitz A Baryawno N Rhee C Oki T Grace E Soled HJ Milosevic J Sykes DB Hsu PP Vander Heiden MG Vidoudez C Trauger SA Haigis MC Scadden DT Induction of a timed metabolic collapse to overcome cancer chemoresistance Cell Metab 2020 32 391 403.e6 10.1016/j.cmet.2020.07.009 32763164
van Gastel N, Spinelli JB, Sharda A, Schajnovitz A, Baryawno N, Rhee C, Oki T, Grace E, Soled HJ, Milosevic J, Sykes DB, Hsu PP, Vander Heiden MG, Vidoudez C, Trauger SA, Haigis MC, Scadden DT. Induction of a timed metabolic collapse to overcome cancer chemoresistance. Cell Metab. 2020;32:391-403.e6. 10.1016/j.cmet.2020.07.009.32763164 10.1016/j.cmet.2020.07.009
127. Ma G Zhang Z Li P Zhang Z Zeng M Liang Z Li D Wang L Chen Y Liang Y Niu H Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment Cell Commun Signal CCS 2022 20 114 10.1186/s12964-022-00909-0 35897036
Ma G, Zhang Z, Li P, Zhang Z, Zeng M, Liang Z, Li D, Wang L, Chen Y, Liang Y, Niu H. Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment. Cell Commun Signal CCS. 2022;20:114. 10.1186/s12964-022-00909-0.35897036 10.1186/s12964-022-00909-0
128. Sornsuvit C Komindr S Chuncharunee S Wanikiat P Archararit N Santanirand P Pilot Study: effects of parenteral glutamine dipeptide supplementation on neutrophil functions and prevention of chemotherapy-induced side-effects in acute myeloid leukaemia patients J Int Med Res 2008 36 1383 1391 10.1177/147323000803600628 19094450
Sornsuvit C, Komindr S, Chuncharunee S, Wanikiat P, Archararit N, Santanirand P. Pilot Study: effects of parenteral glutamine dipeptide supplementation on neutrophil functions and prevention of chemotherapy-induced side-effects in acute myeloid leukaemia patients. J Int Med Res. 2008;36:1383–91. 10.1177/147323000803600628.19094450 10.1177/147323000803600628
129. Liu P-S Wang H Li X Chao T Teav T Christen S Di Conza G Cheng W-C Chou C-H Vavakova M Muret C Debackere K Mazzone M Huang H-D Fendt S-M Ivanisevic J Ho P-C α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming Nat Immunol 2017 18 985 994 10.1038/ni.3796 28714978
Liu P-S, Wang H, Li X, Chao T, Teav T, Christen S, Di Conza G, Cheng W-C, Chou C-H, Vavakova M, Muret C, Debackere K, Mazzone M, Huang H-D, Fendt S-M, Ivanisevic J, Ho P-C. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol. 2017;18:985–94. 10.1038/ni.3796.28714978 10.1038/ni.3796
