Abstract

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.

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Acknowledgements

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

Author notes

    • Tomas Vilimas
    •  & Joaquina Mascarenhas

    These authors contributed equally to this work.

    • Tomas Vilimas

    Present address: Department of Medicine, Northwestern University School of Medicine, 303 East Superior Street, Chicago, Illinois 60610, USA.

Affiliations

  1. Department of Medicine, Section of Rheumatology, University of Chicago, 5841 South Maryland Avenue Chicago, Illinois 60637, USA.

    • Tomas Vilimas
    • , Malay Mandal
    • , Silvia Buonamici
    • , Fanyong Meng
    • , Benjamín Thompson
    • , Sami Macaroun
    • , Maria-Luisa Alegre
    •  & Iannis Aifantis
  2. Oncology Institute, Loyola University Medical Center, 2160 South First Avenue, Maywood, Illinois 60153, USA.

    • Joaquina Mascarenhas
    •  & Lucio Miele
  3. Institute for Cancer Genetics, Columbia University, 1130 St. Nicholas Avenue, New York, New York 10032, USA.

    • Teresa Palomero
    •  & Adolfo Ferrando
  4. Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.

    • Silvia Buonamici
    • , Benjamín Thompson
    •  & Iannis Aifantis
  5. Department of Pathology, University of Chicago, 5841 S. Maryland Avenue, Chicago, Illinois 60637, USA.

    • Christina Spaulding
    •  & Barbara L Kee

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Iannis Aifantis.

Supplementary information

PDF files

  1. 1.

    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.

  2. 2.

    Supplementary Fig. 2

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

  3. 3.

    Supplementary Fig. 3

    γ-secretase inhibitors block NF-γB activation in KOPTK1 T-ALL cells.

  4. 4.

    Supplementary Fig. 4

    Effects of γ-secretase inhibitors on NF-κB activation and growth of T-ALL cell lines.

  5. 5.

    Supplementary Fig. 5

    Active, mutated Notch1 interacts with the IKK complex in KOPTK1 T-ALL cells.

  6. 6.

    Supplementary Fig. 6

    Activation of the NF-κB pathway in human T-ALL lines harboring activating Notch1 mutations.

  7. 7.

    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

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DOI

https://doi.org/10.1038/nm1524

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