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

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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.


  1. Hori, K., Sen, A. & Artavanis-Tsakonas, S. Notch signaling at a glance. J. Cell Sci. 126, 2135–2140 (2013).

    Article  CAS  Google Scholar 

  2. Rothenberg, E.V., Moore, J.E. & Yui, M.A. Launching the T-cell-lineage developmental programme. Nat. Rev. Immunol. 8, 9–21 (2008).

    Article  CAS  Google Scholar 

  3. Thompson, P.K. & Zuniga-Pflucker, J.C. On becoming a T cell, a convergence of factors kick it up a Notch along the way. Semin. Immunol. 23, 350–359 (2011).

    Article  CAS  Google Scholar 

  4. Ciofani, M. & Zuniga-Pflucker, J.C. Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat. Immunol. 6, 881–888 (2005).

    Article  CAS  Google Scholar 

  5. Weng, A.P. et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306, 269–271 (2004).

    Article  CAS  Google Scholar 

  6. Selkoe, D. & Kopan, R. Notch and presenilin: regulated intramembrane proteolysis links development and degeneration. Annu. Rev. Neurosci. 26, 565–597 (2003).

    Article  CAS  Google Scholar 

  7. Palomero, T. et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat. Med. 13, 1203–1210 (2007).

    Article  CAS  Google Scholar 

  8. Chiang, M.Y. et al. Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. J. Clin. Invest. 118, 3181–3194 (2008).

    Article  CAS  Google Scholar 

  9. Milano, J. et al. Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol. Sci. 82, 341–358 (2004).

    Article  CAS  Google Scholar 

  10. Palomero, T. et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc. Natl. Acad. Sci. USA 103, 18261–18266 (2006).

    Article  CAS  Google Scholar 

  11. Buzzai, M. et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation. Oncogene 24, 4165–4173 (2005).

    Article  CAS  Google Scholar 

  12. Wise, D.R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. USA 105, 18782–18787 (2008).

    Article  CAS  Google Scholar 

  13. Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    Article  CAS  Google Scholar 

  14. Schroeter, E.H., Kisslinger, J.A. & Kopan, R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 393, 382–386 (1998).

    Article  CAS  Google Scholar 

  15. Locasale, J.W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43, 869–874 (2011).

    Article  CAS  Google Scholar 

  16. Robinson, M.M. et al. Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES). Biochem. J. 406, 407–414 (2007).

    Article  CAS  Google Scholar 

  17. Tennant, D.A., Duran, R.V. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nat. Rev. Cancer 10, 267–277 (2010).

    Article  CAS  Google Scholar 

  18. Homminga, I. et al. Characterization of a pediatric T-cell acute lymphoblastic leukemia patient with simultaneous LYL1 and LMO2 rearrangements. Haematologica 97, 258–261 (2012).

    Article  CAS  Google Scholar 

  19. Medyouf, H. et al. Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss. Blood 115, 1175–1184 (2010).

    Article  CAS  Google Scholar 

  20. Knoechel, B. et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat. Genet. 46, 364–370 (2014).

    Article  CAS  Google Scholar 

  21. Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).

    Article  CAS  Google Scholar 

  22. Zhou, S. et al. Autophagy in tumorigenesis and cancer therapy: Dr. Jekyll or Mr. Hyde? Cancer Lett. 323, 115–127 (2012).

    Article  CAS  Google Scholar 

  23. Elstrom, R.L. et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64, 3892–3899 (2004).

    Article  CAS  Google Scholar 

  24. Bauer, D.E., Hatzivassiliou, G., Zhao, F., Andreadis, C. & Thompson, C.B. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314–6322 (2005).

    Article  CAS  Google Scholar 

  25. Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).

    Article  CAS  Google Scholar 

  26. Tong, X., Zhao, F. & Thompson, C.B. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr. Opin. Genet. Dev. 19, 32–37 (2009).

    Article  CAS  Google Scholar 

  27. Guo, K. et al. Disruption of peripheral leptin signaling in mice results in hyperleptinemia without associated metabolic abnormalities. Endocrinology 148, 3987–3997 (2007).

    Article  CAS  Google Scholar 

  28. Trotman, L.C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, e59 (2003).

    Article  Google Scholar 

  29. Kimbrel, E.A., Davis, T.N., Bradner, J.E. & Kung, A.L. In vivo pharmacodynamic imaging of proteasome inhibition. Mol. Imaging 8, 140–147 (2009).

    Article  CAS  Google Scholar 

  30. Gentleman, R.C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004).

    Article  Google Scholar 

  31. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  Google Scholar 

  32. Campos-Sandoval, J.A. et al. Expression of functional human glutaminase in baculovirus system: affinity purification, kinetic and molecular characterization. Int. J. Biochem. Cell Biol. 39, 765–773 (2007).

    Article  CAS  Google Scholar 

  33. Heckl, D. et al. Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing. Nat. Biotechnol. 32, 941–946 (2014).

    Article  CAS  Google Scholar 

  34. Chou, T.C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70, 440–446 (2010).

    Article  CAS  Google Scholar 

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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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Authors and Affiliations



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).

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