Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia


T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively active Notch1 activates the NF-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-κB in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-κB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These findings identify NF-κB as one of the major mediators of Notch1-induced transformation and suggest that the NF-κB pathway is a potential target of future therapies of T-ALL.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Notch1-IC causes increased expression of target genes of NF-κB in bone marrow hematopoietic progenitors.
Figure 2: Notch1-IC activates the NF-κB pathway by interacting with the IKK complex and by increasing transcription of NFKB2 and RELB.
Figure 3: T-ALL–derived mutant forms of Notch1 can activate NF-κB.
Figure 4: Human T-ALL lines are susceptible to NF-κB inhibition.
Figure 5: NF-κB is important but not sufficient for T-ALL development in vivo.

Accession codes




  1. Karin, M. & Greten, F.R. NF-κB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5, 749–759 (2005).

    CAS  Article  Google Scholar 

  2. Karin, M. Nuclear factor-κB in cancer development and progression. Nature 441, 431–436 (2006).

    CAS  Article  Google Scholar 

  3. Portis, T., Harding, J.C. & Ratner, L. The contribution of NF-κB activity to spontaneous proliferation and resistance to apoptosis in human T-cell leukemia virus type 1 Tax-induced tumors. Blood 98, 1200–1208 (2001).

    CAS  Article  Google Scholar 

  4. Carrasco, D., Rizzo, C.A., Dorfman, K. & Bravo, R. The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice. EMBO J. 15, 3640–3650 (1996).

    CAS  Article  Google Scholar 

  5. Bellavia, D. et al. Constitutive activation of NF-κB and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J. 19, 3337–3348 (2000).

    CAS  Article  Google Scholar 

  6. Mandal, M. et al. The BCL2A1 gene as a pre-T cell receptor-induced regulator of thymocyte survival. J. Exp. Med. 201, 603–614 (2005).

    CAS  Article  Google Scholar 

  7. Vacca, A. et al. Notch3 and pre-TCR interaction unveils distinct NF-κB pathways in T-cell development and leukemia. EMBO J. 25, 1000–1008 (2006).

    CAS  Article  Google Scholar 

  8. Wilson, J.J. & Kovall, R.A. Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell 124, 985–996 (2006).

    CAS  Article  Google Scholar 

  9. Nam, Y., Sliz, P., Song, L., Aster, J.C. & Blacklow, S.C. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124, 973–983 (2006).

    CAS  Article  Google Scholar 

  10. Radtke, F., Schweisguth, F. & Pear, W. The Notch 'gospel'. EMBO Rep. 6, 1120–1125 (2005).

    CAS  Article  Google Scholar 

  11. Pear, W.S. et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183, 2283–2291 (1996).

    CAS  Article  Google Scholar 

  12. Allman, D., Li, J. & Hardy, R.R. Commitment to the B lymphoid lineage occurs before DH-JH recombination. J. Exp. Med. 189, 735–740 (1999).

    CAS  Article  Google Scholar 

  13. Beverly, L.J. & Capobianco, A.J. Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis. Cancer Cell 3, 551–564 (2003).

    CAS  Article  Google Scholar 

  14. 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 

  15. O'Neil, J. et al. Activating Notch1 mutations in mouse models of T-ALL. Blood 107, 781–785 (2006).

    CAS  Article  Google Scholar 

  16. Pui, J.C. et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11, 299–308 (1999).

    CAS  Article  Google Scholar 

  17. Allman, D. et al. Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells. J. Exp. Med. 194, 99–106 (2001).

    CAS  Article  Google Scholar 

  18. Schmitt, T.M., Ciofani, M., Petrie, H.T. & Zuniga-Pflucker, J.C. Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions. J. Exp. Med. 200, 469–479 (2004).

    CAS  Article  Google Scholar 

  19. Aifantis, I., Gounari, F., Scorrano, L., Borowski, C. & von Boehmer, H. Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-κB and NFAT. Nat. Immunol. 2, 403–409 (2001).

    CAS  Article  Google Scholar 

  20. Voll, R.E. et al. NF-κB activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development. Immunity 13, 677–689 (2000).

    CAS  Article  Google Scholar 

  21. Reizis, B. & Leder, P. Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. Genes Dev. 16, 295–300 (2002).

    CAS  Article  Google Scholar 

  22. Fan, Y., Rayet, B. & Gelinas, C. Divergent C-terminal transactivation domains of Rel/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes. Oncogene 23, 1030–1042 (2004).

    CAS  Article  Google Scholar 

  23. Maillard, I. et al. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood 104, 1696–1702 (2004).

    CAS  Article  Google Scholar 

  24. Oswald, F., Liptay, S., Adler, G. & Schmid, R.M. NF-κB2 is a putative target gene of activated Notch-1 via RBP-Jκ. Mol. Cell. Biol. 18, 2077–2088 (1998).

    CAS  Article  Google Scholar 

  25. 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 γ-secretase inhibitors. Leukemia 20, 1279–1287 (2006).

    CAS  Article  Google Scholar 

  26. Burke, J.R. et al. BMS-345541 is a highly selective inhibitor of IκB kinase that binds at an allosteric site of the enzyme and blocks NF-κB-dependent transcription in mice. J. Biol. Chem. 278, 1450–1456 (2003).

    CAS  Article  Google Scholar 

  27. Wahl, C., Liptay, S., Adler, G. & Schmid, R.M. Sulfasalazine: a potent and specific inhibitor of nuclear factor κB. J. Clin. Invest. 101, 1163–1174 (1998).

    CAS  Article  Google Scholar 

  28. Spano, J.P., Bay, J.O., Blay, J.Y. & Rixe, O. Proteasome inhibition: a new approach for the treatment of malignancies. Bull. Cancer 92, 945–952 (2005).

    CAS  Google Scholar 

  29. Chauhan, D., Hideshima, T., Mitsiades, C., Richardson, P. & Anderson, K.C. Proteasome inhibitor therapy in multiple myeloma. Mol. Cancer Ther. 4, 686–692 (2005).

    CAS  Article  Google Scholar 

  30. Boothby, M.R., Mora, A.L., Scherer, D.C., Brockman, J.A. & Ballard, D.W. Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF)-κB. J. Exp. Med. 185, 1897–1907 (1997).

    CAS  Article  Google Scholar 

  31. 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 

  32. Klinakis, A. et al. Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proc. Natl. Acad. Sci. USA 103, 9262–9267 (2006).

    CAS  Article  Google Scholar 

  33. Wang, J. et al. Human Notch-1 inhibits NF-κB activity in the nucleus through a direct interaction involving a novel domain. J. Immunol. 167, 289–295 (2001).

    CAS  Article  Google Scholar 

  34. Espinosa, L., Ingles-Esteve, J., Robert-Moreno, A. & Bigas, A. IκBα and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between Notch and NFκB pathways. Mol. Biol. Cell 14, 491–502 (2003).

    CAS  Article  Google Scholar 

  35. Oakley, F. et al. Basal expression of IκBα is controlled by the mammalian transcriptional repressor RBP-J (CBF1) and its activator Notch1. J. Biol. Chem. 278, 24359–24370 (2003).

    CAS  Article  Google Scholar 

  36. Shin, H.M. et al. Notch1 augments NF-κB activity by facilitating its nuclear retention. EMBO J. 25, 129–138 (2006).

    CAS  Article  Google Scholar 

  37. Aster, J.C. Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: new insights, questions, and opportunities. Int. J. Hematol. 82, 295–301 (2005).

    CAS  Article  Google Scholar 

  38. 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 

  39. Fehling, H.J., Krotkova, A., Saint-Ruf, C. & von Boehmer, H. Crucial role of the pre-T-cell receptor α gene in development of αβ but not γδ T cells. Nature 375, 795–798 (1995).

    CAS  Article  Google Scholar 

  40. Campese, A.F. et al. Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling. Blood 108, 305–310 (2006).

    CAS  Article  Google Scholar 

  41. Ory, D.S., Neugeboren, B.A. & Mulligan, R.C. A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes. Proc. Natl. Acad. Sci. USA 93, 11400–11406 (1996).

    CAS  Article  Google Scholar 

  42. Borowski, C., Li, X., Aifantis, I., Gounari, F. & Von Boehmer, H. Pre-TCRα and TCRα are not interchangeable partners of TCRβ during T lymphocyte development. J. Exp. Med. 199, 607–615 (2004).

    CAS  Article  Google Scholar 

  43. El Andaloussi, A. et al. Hedgehog signaling controls thymocyte progenitor homeostasis and differentiation in the thymus. Nat. Immunol. 7, 418–426 (2006).

    CAS  Article  Google Scholar 

  44. Palomero, T. et al. Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia. Blood 108, 986–992 (2006).

    CAS  Article  Google Scholar 

  45. Nickoloff, B.J. et al. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-κB and PPARγ. Cell Death Differ. 9, 842–855 (2002).

    CAS  Article  Google Scholar 

Download references


We thank R. Duggan, J. Marvin, V. Bindokas, C. Labno, S. Li, J. Theusch and H. McDonald for technical support. W. Pear (University of Pennsylvania) provided the DN-MAML1 vector; C. Borowski (Harvard Medical School) provided the IkBαDN vector; and C. Gelinas (Cancer Institute of New Jersey) provided the Ikbka (IKKβSS-EE) retroviral plasmid. We also acknowledge A. Montag for interpretation of histological samples. I.A. is supported by the Sidney Kimmel Foundation for Cancer Research, the G&P Foundation for Cancer Research and by US National Institutes of Health grant R01CA105129. L.M. is supported by National Institutes of Health grants R01CA84065 and P01AG025531. B.L.K. is supported by the Concern Foundation and the Leukemia Research Foundation.

Author information

Authors and Affiliations



I.A. supervised the project. T.V., J.M., T.P., M.M., S.B., F.M., B.T., C.S. and S.M. conducted experiments. M.-L.A. helped with the Ikbia experiments. B.L.K. supervised the EMSA experiments. A.F. supervised the CHIP-on-chip experiments. L.M. supervised experiments and helped with the editing of the manuscript. I.A. and T.V. cowrote the manuscript.

Corresponding author

Correspondence to Iannis Aifantis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Expression of Notch1-IC in bone marrow lineage-negative progenitors results in activation of a T lineage transcriptional program and down-regulation of myeloid and B cell genes. (PDF 403 kb)

Supplementary Fig. 2

Gene expression and proliferation of Ptcra−/− Notch1-IC+ bone marrow progenitors is comparable to that of wt-Notch1-IC+ progenitors. (PDF 158 kb)

Supplementary Fig. 3

γ-secretase inhibitors block NF-γB activation in KOPTK1 T-ALL cells. (PDF 429 kb)

Supplementary Fig. 4

Effects of γ-secretase inhibitors on NF-κB activation and growth of T-ALL cell lines. (PDF 266 kb)

Supplementary Fig. 5

Active, mutated Notch1 interacts with the IKK complex in KOPTK1 T-ALL cells. (PDF 109 kb)

Supplementary Fig. 6

Activation of the NF-κB pathway in human T-ALL lines harboring activating Notch1 mutations. (PDF 403 kb)

Supplementary Table 1

Notch1-IC activates a T lineage transcriptional profile and suppresses expression of B cell and myeloid-specific genes in bone marrow progenitors (PDF 41 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vilimas, T., Mascarenhas, J., Palomero, T. et al. Targeting the NF-κB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13, 70–77 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing