Abstract 3723: SIRT1 is a novel therapeutic target in T-ALL

Abstract

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a NOTCH1-driven aggressive disease that requires treatment with intensified chemotherapy. Still, 20-50% of patients relapse and ultimately die, highlighting the need to identify novel therapeutic targets. We previously demonstrated the importance of NOTCH1-driven metabolic pathways in the response to anti-NOTCH1 therapies (gamma-secretase inhibitors, GSIs), and identified both glutaminolysis and autophagy as therapeutic targets that are highly synergistic with NOTCH1 inhibition in T-ALL in vivo. Moreover, epigenetic plasticity has also been proposed to mediate resistance to GSIs. Thus, we postulated that central regulators that control both the metabolic and epigenetic status of cells could act as master regulators of NOTCH1-induced transformation and might lead us to the identification of novel therapeutic targets in this disease. In this context, our results have identified the SIRT1 histone deacetylase, a central epigenetic and metabolic regulator, as a key player in T-ALL. Analyses of gene expression profiling data from T-ALL patients revealed a significant upregulation of SIRT1 in T-ALL patients. Consistently, SIRT1 protein levels are significantly upregulated in T-ALL cells as compared to normal human thymus. Next, and to formally test the effects of Sirt1 on T-cell transformation, we generated NOTCH1-driven primary T-ALLs from different Sirt1 genetic backgrounds. In this context, our results demonstrate that Sirt1 genetic overexpression leads to accelerated kinetics of NOTCH1-induced T-ALL and promotes resistance to GSI treatment in T-ALL in vivo in a deacetylase-dependent manner. Conversely, germinal loss of Sirt1 leads to delayed T-ALL development and reduced disease penetrance. Moreover, pharmacological inhibition of SIRT1 with Tenovin-6 shows anti-leukemic and synergistic effects with NOTCH1 inhibition in T-ALL cell lines in vitro. Finally, genetic deletion of Sirt1 in already established primary isogenic Sirt1 conditional knockout leukemias leads to significant and highly synergistic anti-leukemic effects with GSI treatment in vivo, resulting in complete cure of 10% of mice. Mechanistically, acute deletion of Sirt1 leads to broad transcriptional changes characterized by a block in mTOR signaling, suggesting leukemia cells suffer a metabolic crisis upon Sirt1 loss. Consistently, acute deletion of Sirt1 results in prominent global metabolic changes in glycolysis, TCA cycle and fatty acid oxidation pathways. Specifically, Sirt1 loss results in a significant glycolytic block with concomitant activation of AMPK, resulting in markedly cytotoxic effects. Overall, our results reveal SIRT1 as a critical major player in T-ALL; unveil an oncogenic role for Sirt1 in T-ALL generation and progression; demonstrate that Sirt1 mediates resistance to anti-NOTCH1 therapies; and uncover Sirt1 as a novel therapeutic target for the treatment of T-ALL. Citation Format: Olga Lancho, Victoria da Silva-Diz, Shirley Luo, Amarthya Singh, Hossein Khiabanian, Daniel Herranz. SIRT1 is a novel therapeutic target in T-ALL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3723.