Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia

Nguyen, Tien-Tuan; Nokin, Marie-Julie; Terés, Silvia; Tomé, Mercedes; Bodineau, Clément; Galmar, Oriane; Pasquet, Jean‐Max; Rousseau, Benoı̂t; Liempd, Sebastian van; Falcón‐Pérez, Juan Manuel; Richard, Élodie; Muzotte, Elodie; Rezvani, Hamid-Reza; Priault, Muriel; Bouchecareilh, Marion; Redonnet‐Vernhet, Isabelle; Calvo, Julien; Uzan, Benjamin; Pflumio, Françoise; Fuentes, Patricia; Toribio, María Luisa; Khatib, Abdel‐Majid; Soubeyran, Pierre; Murdoch, Piedad del Socorro; Durán, Raúl V.

doi:10.1002/1878-0261.12877

Cited by 22 publications

(20 citation statements)

References 29 publications

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“…In nutritional deficiency, macromolecule decomposition through autophagy and glutamine synthetase–mediated synthesis from glutamate are two sources of glutamine 40,42 . Downregulation of glutamine synthetase blocks glutamine anabolism in Notch receptor 1 (NOTCH1)–positive T‐cell acute lymphoblastic leukemia (T‐ALL), resulting in complete dependence of T‐ALL on extracellular glutamine both in vitro and in vivo 55 …”

Section: Glutaminementioning

confidence: 99%

“…Glutaminolysis is an essential energy source for supporting cell proliferation in AML cells harboring AF9–mixed lineage leukemia rearrangement and ecotropic viral integration site‐1 (EVI1) overexpression 69 . In T‐ALL, glutaminolysis is promoted by the overexpression of NOTCH1 to power the TCA cycle and activate the mTORC1 pathway 55,70 . Sirtuin 3 and 4 from the sirtuin family of class III histone deacetylases regulate glutamine metabolism in lymphoma in different ways.…”

Section: Glutaminementioning

confidence: 99%

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Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma

Liao

Chang

et al. 2022

Immunol Cell Biol

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Leukemia and lymphoma—the most common hematological malignant diseases—are often accompanied by complications such as drug resistance, refractory diseases and relapse. Amino acids (AAs) are important energy sources for malignant cells. Tumor‐mediated AA metabolism is associated with the immunosuppressive properties of the tumor microenvironment, thereby assisting malignant cells to evade immune surveillance. Targeting abnormal AA metabolism in the tumor microenvironment may be an effective therapeutic approach to address the therapeutic challenges of leukemia and lymphoma. Here, we review the effects of glutamine, arginine and tryptophan metabolism on tumorigenesis and immunomodulation, and define the differences between tumor cells and immune effector cells. We also comment on treatments targeting these AA metabolism pathways in lymphoma and leukemia and discuss how these treatments have profound adverse effects on tumor cells, but leave the immune cells unaffected or mildly affected.

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Section: Glutaminementioning

confidence: 99%

Section: Glutaminementioning

confidence: 99%

Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma

Liao

Chang

et al. 2022

Immunol Cell Biol

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“…This target’s the unique vulnerability of B-ALL cells without impacting the non-transformed cells. Glucose utilization is important for the survival of B-ALL cells, whereas NOTCH1 activation in T-ALL leads to a metabolic switch from glycolysis to glutaminolysis ( 71 , 72 ). The reduced glycolysis in T-ALL cells compared to normal T-cells can be attributed to Notch1-mediated AMPK activation ( 73 ).…”

Section: Metabolism In Lymphoid Leukemiamentioning

confidence: 99%

Deciphering Metabolic Adaptability of Leukemic Stem Cells

et al. 2022

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Therapeutic targeting of leukemic stem cells is widely studied to control leukemia. An emerging approach gaining popularity is altering metabolism as a potential therapeutic opportunity. Studies have been carried out on hematopoietic and leukemic stem cells to identify vulnerable pathways without impacting the non-transformed, healthy counterparts. While many metabolic studies have been conducted using stem cells, most have been carried out in vitro or on a larger population of progenitor cells due to challenges imposed by the low frequency of stem cells found in vivo. This creates artifacts in the studies carried out, making it difficult to interpret and correlate the findings to stem cells directly. This review discusses the metabolic difference seen between hematopoietic stem cells and leukemic stem cells across different leukemic models. Moreover, we also shed light on the advancements of metabolic techniques and current limitations and areas for additional research of the field to study stem cell metabolism.

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“…This metabolic reprogramming was shown to induce resistance to anti-Notch1 therapy (141). Consequently, the inhibition of glutaminolysis and mTOR was proposed as a potential strategy against Notch1driven and, even, against anti-Notch1 therapy resistant ALL (141,142). GCs not only suppress glycolysis, but also prevent the entry of glutamine into TCA cycle (44).…”

Section: Metabolic Re-programming and Upregulation Of The Pi3k/akt/mtmentioning

confidence: 99%

Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol

et al. 2021

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Glucocorticoids (GCs) are a central component of multi-drug treatment protocols against T and B acute lymphoblastic leukemia (ALL), which are used intensively during the remission induction to rapidly eliminate the leukemic blasts. The primary response to GCs predicts the overall response to treatment and clinical outcome. In this review, we have critically analyzed the available data on the effects of GCs on sensitive and resistant leukemic cells, in order to reveal the mechanisms of GC resistance and how these mechanisms may determine a poor outcome in ALL. Apart of the GC resistance, associated with a decreased expression of receptors to GCs, there are several additional mechanisms, triggered by alterations of different signaling pathways, which cause the metabolic reprogramming, with an enhanced level of glycolysis and oxidative phosphorylation, apoptosis resistance, and multidrug resistance. Due to all this, the GC-resistant ALL show a poor sensitivity to conventional chemotherapeutic protocols. We propose pharmacological strategies that can trigger alternative intracellular pathways to revert or overcome GC resistance. Specifically, we focused our search on drugs, which are already approved for treatment of other diseases and demonstrated anti-ALL effects in experimental pre-clinical models. Among them are some “truly” re-purposed drugs, which have different targets in ALL as compared to other diseases: cannabidiol, which targets mitochondria and causes the mitochondrial permeability transition-driven necrosis, tamoxifen, which induces autophagy and cell death, and reverts GC resistance through the mechanisms independent of nuclear estrogen receptors (“off-target effects”), antibiotic tigecycline, which inhibits mitochondrial respiration, causing energy crisis and cell death, and some anthelmintic drugs. Additionally, we have listed compounds that show a classical mechanism of action in ALL but are not used still in treatment protocols: the BH3 mimetic venetoclax, which inhibits the anti-apoptotic protein Bcl-2, the hypomethylating agent 5-azacytidine, which restores the expression of the pro-apoptotic BIM, and compounds targeting the PI3K-Akt-mTOR axis. Accordingly, these drugs may be considered for the inclusion into chemotherapeutic protocols for GC-resistant ALL treatments.

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Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1‐driven acute lymphoblastic leukemia

Cited by 22 publications

References 29 publications

Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma

Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma

Deciphering Metabolic Adaptability of Leukemic Stem Cells

Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol

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