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 invitro and invivo. 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.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) appears upon the malignant transformation of a T-cell progenitor
The analysis of Notch1-target genes and gene expression programs controlled by Notch1 showed that Notch1 promotes leukemic cell growth via direct transcriptional upregulation of genes involved in ribosome biosynthesis, amino acid metabolism, protein translation, and nucleotide synthesis
Beyond confirming the model by which Notch1 induces glutaminolysis, our results propose that Notch1 executes a program leading to the upregulation of glutamine catabolism and cell growth signaling, and blocking glutamine anabolism, which leads to glutamine addiction in Notch1-driven leukemia
Summary
T-cell acute lymphoblastic leukemia (T-ALL) appears upon the malignant transformation of a T-cell progenitor. In the case of Notch1-driven T-ALL, very little has been described regarding the participation of glutamine in Notch1-mediated T-cell malignant transformation or even in other types of cancer. A comparative metabolomic study performed in myeloid leukemic cells reported that the upregulation of Notch signaling decreases the expression of GLS and GDH and decreases glutamine consumption [12]. We observed that Notch upregulation leads to proteosomal degradation of GS, responsible for glutamine addiction in Notch1-activated leukemic cells. Notch induces the upregulation of GLS and the subsequent activation of mTORC1 signaling pathway, leading to mTORC1 dependency in Notch-driven T-ALL. Beyond confirming the model by which Notch induces glutaminolysis, our results propose that Notch executes a program leading to the upregulation of glutamine catabolism and cell growth signaling, and blocking glutamine anabolism, which leads to glutamine addiction in Notch1-driven leukemia. Our results pointed at the potential therapeutic benefits of targeting glutamine availability and mTORC1 signaling in Notch1-positive T-ALL patients
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