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Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia

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Abstract

Activating mutations in NOTCH1 are common in T cell acute lymphoblastic leukemia (T-ALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of the response to anti-NOTCH1 therapies in vivo. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown, with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapy in mice harboring T-ALL. Moreover, we demonstrate that Pten loss upregulates glycolysis and consequently rescues leukemic cell metabolism, thereby abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL.

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Figure 1: Pten loss induces resistance to GSI treatment in vivo.
Figure 2: Metabolic profiling analysis and metabolic rescue of NOTCH1 inhibition in T-ALL.
Figure 3: Autophagy supports leukemic cell growth in response to NOTCH1 inhibition.
Figure 4: Glucose and glutamine metabolic flux analysis of T-ALL cells upon NOTCH1 inhibition and Pten loss.
Figure 5: The antileukemic effects of GSI in Pten-positive leukemias can be rescued by myristoylated AKT (MyrAKT), GLS and PKM2 overexpression.
Figure 6: Synergistic antileukemic effects of GLS inhibition and GSI treatment in T-ALL.

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Change history

  • 23 October 2015

    Mouse images are duplicated in Fig. 6e (day 0 Vehicle and day 0 BPTES) and in Fig. 6f (day 0 DBZ + BPTES and day 6 DBZ + BPTES). The authors made these errors in assembling the figure panels. The authors have now supplied corrected versions of these panels, in which the correct micrographs for Fig. 6e (day 0 BPTES) and Fig. 6f (day 6 DBZ + BPTS) are included. These errors do not affect the data shown in the graphs in Fig. 6e,f. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We are grateful to J. Aster (Brigham and Women's Hospital, Harvard Medical School) for the MigR1-NOTCH1 L1601P ΔPEST vector, D. Vignali (University of Pittsburgh) for the pMSCV-mCherry FP vector, W. Pear (Abramson Family Cancer Research Institute, University of Pennsylvania) for the MigR1 vector, B. Ebert (Dana-Farber Cancer Research Institute) for the pL-CRISPR.EFS.GFP vector, P. Pandolfi (Beth Israel Deaconess Medical Center, Harvard Medical School) for the Pten conditional knockout mouse, T. Ludwig (Columbia University Medical Center) for the Rosa26Cre-ERT2/+ mouse, M. Komatsu (Tokyo Metropolitan Institute of Medical Science) for the Atg7 conditional knockout mouse, S. Indraccolo (Istituto di Ricovero e Cura a Carattere Scientifico) for xenograft T-ALL cells and R. Baer and C. Lopez-Otin for helpful discussions and revision of the manuscript. This work was supported by the US National Institutes of Health grants R01CA129382 and CA120196, the Stand Up To Cancer Innovative Research Award and the Swim Across America Foundation (A.A.F.). J.M. and J.M.M. were supported by CVI-6656 (Junta de Andalucía, Spain). D.H. is supported by the Leukemia and Lymphoma Society. M.S.-M. and A.A.W. are supported by the Rally Foundation. L.B. is supported by the Lymphoma Research Foundation.

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Contributions

D.H. carried out most of the experiments. A.A.-I. analyzed gene expression profile signatures. J.S. performed metabolic studies. M.S.-M. performed some in vivo and in vitro drug response analyses. L.B. analyzed PTEN levels by intracellular FACS staining. V.T. generated some of the NOTCH1-induced primary leukemias. L.X. performed some animal studies with D.H. A.A.W. performed some experiments with human primary T-ALL samples. M.C. conducted histological evaluation of tumor development and response to therapy. J.E.H. performed some in vivo experiments. J.M. and J.M.M. contributed reagents. S.R. generated the Gls conditional knockout mice. A.L.K. conceived and supervised bioimaging studies. C.C.-C. supervised histological analyses. R.J.D. supervised metabolic isotope tracing analyses. A.A.F designed the study, supervised research and wrote the manuscript with D.H.

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Correspondence to Adolfo A Ferrando.

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Herranz, D., Ambesi-Impiombato, A., Sudderth, J. et al. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat Med 21, 1182–1189 (2015). https://doi.org/10.1038/nm.3955

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