Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia


Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as γ-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.

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Figure 1: PTEN loss and AKT activation in GSI-resistant T-ALLs.
Figure 2: PTEN loss and AKT activation induce GSI resistance in T-ALL.
Figure 3: NOTCH1 regulates PTEN expression, AKT signaling and glucose metabolism.
Figure 4: HES1 and MYC regulate PTEN expression downstream of NOTCH1.
Figure 5: Interaction of Notch and Pten-PI3K-Akt signaling in growth control and tumorigenesis in Drosophila.
Figure 6: Transcriptional networks downstream of NOTCH1 in T-ALL and effects of pharmacologic inhibition of AKT in T-ALL cells.

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  1. 1

    Grabher, C., von Boehmer, H. & Look, A.T. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat. Rev. Cancer 6, 347–359 (2006).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Stylianou, S., Clarke, R.B. & Brennan, K. Aberrant activation of Notch signaling in human breast cancer. Cancer Res. 66, 1517–1525 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Purow, B.W. et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 65, 2353–2363 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Pahlman, S., Stockhausen, M.T., Fredlund, E. & Axelson, H. Notch signaling in neuroblastoma. Semin. Cancer Biol. 14, 365–373 (2004).

    CAS  Article  Google Scholar 

  6. 6

    Wen, C., Metzstein, M.M. & Greenwald, I. SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling. Development 124, 4759–4767 (1997).

    CAS  PubMed  Google Scholar 

  7. 7

    Struhl, G. & Greenwald, I. Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila. Proc. Natl. Acad. Sci. USA 98, 229–234 (2001).

    CAS  Article  Google Scholar 

  8. 8

    De Strooper, B. et al. A presenilin-1–dependent gamma-secretase–like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Mumm, J.S. et al. A ligand-induced extracellular cleavage regulates gamma-secretase–like proteolytic activation of Notch1. Mol. Cell 5, 197–206 (2000).

    CAS  Article  Google Scholar 

  10. 10

    Hansson, E.M., Lendahl, U. & Chapman, G. Notch signaling in development and disease. Semin. Cancer Biol. 14, 320–328 (2004).

    CAS  Article  Google Scholar 

  11. 11

    Mumm, J.S. & Kopan, R. Notch signaling: from the outside in. Dev. Biol. 228, 151–165 (2000).

    CAS  Article  Google Scholar 

  12. 12

    Seiffert, D. et al. Presenilin-1 and -2 are molecular targets for gamma-secretase inhibitors. J. Biol. Chem. 275, 34086–34091 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Palomero, T. et al. CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors. Leukemia 20, 1279–1287 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Parsons, R. Human cancer, PTEN and the PI-3 kinase pathway. Semin. Cell Dev. Biol. 15, 171–176 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Yilmaz, O.H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Suzuki, A. et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 8, 1169–1178 (1998).

    CAS  Article  Google Scholar 

  17. 17

    Podsypanina, K. et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl. Acad. Sci. USA 96, 1563–1568 (1999).

    CAS  Article  Google Scholar 

  18. 18

    Di Cristofano, A., Pesce, B., Cordon-Cardo, C. & Pandolfi, P.P. Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19, 348–355 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Suzuki, A. et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Hagenbeek, T.J. et al. The loss of PTEN allows TCR alphabeta lineage thymocytes to bypass IL-7 and Pre-TCR–mediated signaling. J. Exp. Med. 200, 883–894 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Chang, H. et al. Analysis of PTEN deletions and mutations in multiple myeloma. Leuk. Res. 30, 262–265 (2006).

    CAS  Article  Google Scholar 

  22. 22

    Aggerholm, A., Gronbaek, K., Guldberg, P. & Hokland, P. Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur. J. Haematol. 65, 109–113 (2000).

    CAS  Article  Google Scholar 

  23. 23

    Sakai, A., Thieblemont, C., Wellmann, A., Jaffe, E.S. & Raffeld, M. PTEN gene alterations in lymphoid neoplasms. Blood 92, 3410–3415 (1998).

    CAS  PubMed  Google Scholar 

  24. 24

    Ferrando, A.A. et al. Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia. Lancet 363, 535–536 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Ferrando, A.A. et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75–87 (2002).

    CAS  Article  Google Scholar 

  26. 26

    Sulis, M.L. & Parsons, R. PTEN: from pathology to biology. Trends Cell Biol. 13, 478–483 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Maehama, T. & Dixon, J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 13375–13378 (1998).

    CAS  Article  Google Scholar 

  28. 28

    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).

    CAS  Article  Google Scholar 

  29. 29

    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).

    CAS  Article  Google Scholar 

  30. 30

    Jarriault, S. et al. Signalling downstream of activated mammalian Notch. Nature 377, 355–358 (1995).

    CAS  Article  Google Scholar 

  31. 31

    Satoh, Y. et al. Roles for c-Myc in self-renewal of hematopoietic stem cells. J. Biol. Chem. 279, 24986–24993 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Weng, A.P. et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 20, 2096–2109 (2006).

    CAS  Article  Google Scholar 

  33. 33

    Kaneta, M. et al. A role for pref-1 and HES-1 in thymocyte development. J. Immunol. 164, 256–264 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Ferres-Marco, D. et al. Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430–436 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Dominguez, M. Interplay between Notch signaling and epigenetic silencers in cancer. Cancer Res. 66, 8931–8934 (2006).

    CAS  Article  Google Scholar 

  36. 36

    Domínguez, M. & de Celis, J.F. A dorsal/ventral boundary established by Notch controls growth and polarity in the Drosophila eye. Nature 396, 276–278 (1998).

    Article  Google Scholar 

  37. 37

    Papayannopoulos, V., Tomlinson, A., Panin, V.M., Rauskolb, C. & Irvine, K.D. Dorsal-ventral signaling in the Drosophila eye. Science 281, 2031–2034 (1998).

    CAS  Article  Google Scholar 

  38. 38

    Cho, K.O. & Choi, K.W. Fringe is essential for mirror symmetry and morphogenesis in the Drosophila eye. Nature 396, 272–276 (1998).

    CAS  Article  Google Scholar 

  39. 39

    DeGraffenried, L.A. et al. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann. Oncol. 15, 1510–1516 (2004).

    CAS  Article  Google Scholar 

  40. 40

    She, Q.B., Solit, D., Basso, A. & Moasser, M.M. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin. Cancer Res. 9, 4340–4346 (2003).

    CAS  PubMed  Google Scholar 

  41. 41

    Xu, Z., Stokoe, D., Kane, L.P. & Weiss, A. The inducible expression of the tumor suppressor gene PTEN promotes apoptosis and decreases cell size by inhibiting the PI3K/Akt pathway in Jurkat T cells. Cell Growth Differ. 13, 285–296 (2002).

    CAS  PubMed  Google Scholar 

  42. 42

    Weinstein, I.B. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297, 63–64 (2002).

    CAS  Article  Google Scholar 

  43. 43

    Weinstein, I.B. & Joe, A.K. Mechanisms of disease: Oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat. Clin. Pract. Oncol. 3, 448–457 (2006).

    CAS  Article  Google Scholar 

  44. 44

    Basso, K. et al. Reverse engineering of regulatory networks in human B cells. Nat. Genet. 37, 382–390 (2005).

    CAS  Article  Google Scholar 

  45. 45

    Li, C. & Wong, W.H. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl. Acad. Sci. USA 98, 31–36 (2001).

    CAS  Article  Google Scholar 

  46. 46

    Schmitt, T.M. & Zuniga-Pflucker, J.C. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17, 749–756 (2002).

    CAS  Article  Google Scholar 

  47. 47

    Ciofani, M. et al. Obligatory role for cooperative signaling by pre-TCR and Notch during thymocyte differentiation. J. Immunol. 172, 5230–5239 (2004).

    CAS  Article  Google Scholar 

  48. 48

    Swainson, L. et al. Glucose transporter 1 expression identifies a population of cycling CD4+ CD8+ human thymocytes with high CXCR4-induced chemotaxis. Proc. Natl. Acad. Sci. USA 102, 12867–12872 (2005).

    CAS  Article  Google Scholar 

  49. 49

    Doughty, C.A. et al. Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood 107, 4458–4465 (2006).

    CAS  Article  Google Scholar 

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We thank A.T. Look (Dana-Farber Cancer Institute) and M. Minden (Ontario Cancer Institute) for valuable clinical samples; D. Ferres-Marco (Instituto de Neurociencias de Alicante) for the GS1D233C line; E. Ballesta (Instituto de Neurociencias de Alicante) for histological sections of dDp110; T. Yoshimori (Kansai Medical University), R. Dalla Favera, W. Ai and D. Accili (Columbia University) and W. Hahn (Dana-Farber Cancer Institute) for reagents; V. Miljkovic for assistance with DNA sequencing and microarray hybridization; and B. Weinstein, R. Baer, T. Diaccovo and C. Lopez-Otin for critical review of the manuscript. This work was supported by the Fondazione Città Della Speranza (G. Basso), the Spanish Ministerio de Educacion y Ciencia and Asociación Española Contra el Cancer (M.D.), NIH grant CA120196, the WOLF Foundation, the Charlotte Geyer Foundation, the Golfers Against Cancer Foundation and the Leukemia and Lymphoma Society (grant 1287-08) (A.A.F.). Adolfo Ferrando is a Leukemia & Lymphoma Society Scholar.

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Correspondence to Maria Dominguez or Adolfo A Ferrando.

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Supplementary Results, Supplementary Discussion, Supplementary Methods, Supplementary Figs. 1–10, Supplementary Tables 1–5, Supplementary Methods (PDF 2893 kb)

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

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