Dataset Information

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

ABSTRACT: The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.

SUBMITTER: Nguyen TL

PROVIDER: S-EPMC8096784 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:We investigated the effects of glutamine (Gln)-enriched nutritional therapy during chemotherapy on the nutritional status and immune function of children with acute lymphoblastic leukemia (ALL).We enrolled 48 children who were newly diagnosed with ALL in our department during the period of 2013.1-2014.12. The patients (follow random number table) were randomly divided into the control group (peptamen) and the treatment group (peptamen + glutamine), 24 cases in each group. The remission induction regimens were all based on VDLP (D) chemotherapy (VCR (Vincrisstine), DNR (Daunomycin), L-ASP (L-Asparagiase), Prednisolone and Dexamethasone). The treatment group received Gln-enriched nutritional therapy every day during the full course of chemotherapy,and the control group is as same as the treatment group except without glutamine. The indicators of general nutritional status, such as weight, height, and triceps skinfold thickness, and the indicators of biochemical tests, such as serum albumin, prealbumin, creatinine-height index, retinol binding protein, and urinary hydroxyproline index, were compared between the two groups at the end of the first, second, third and the fourth week when the chemotherapy was completed. And in the fourth week, flow cytometry was applied to detect the levels of T cell subsets and the activities of natural killer (NK) cells in peripheral blood of the two groups.1. after 4 weeks nutritional therapy, there is no significant difference (p > 0.05) between the two groups of children in weight, height and other indicators. 2. At the end of 2 weeks treatment, the level of prealbumin (PA) and retinol-binding protein (RBP) is higher in treatment group than that in the control group (P <0.05), at the end of 3 weeks treatment, the thickness of triceps skinfold is higher (P <0.05) than that in the control group; 3. At the end of 3 and 4 weeks, the concentrations serum ALB, PA, RBP and UHI were higher than in the control group (P <0.05); 4. There is statistically significant (p < 0.05) between the two groups in edema incidence; 5. At the end of treatment (4 weeks), the percentages of CD3 +, CD4 +, CD4 +/CD8 +, NK cell are significantly decreased in the two groups (P <0.05).Gln-enriched nutritional therapy can effectively improve the systemic nutritional status of children with leukemia, improve immune function.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets