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Abstract

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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Acknowledgements

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.

Author information

Author notes

    • Maria Luisa Sulis
    •  & Maria Cortina

    These authors contributed equally to this work.

Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.

    • Teresa Palomero
    • , Maria Luisa Sulis
    • , Pedro J Real
    • , Kelly Barnes
    • , Ramon Parsons
    •  & Adolfo A Ferrando
  2. Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA.

    • Teresa Palomero
    • , Kristy Brown
    • , Govind Bhagat
    • , Mireia Castillo
    • , Carlos Cordon-Cardo
    •  & Adolfo A Ferrando
  3. Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.

    • Maria Luisa Sulis
    •  & Adolfo A Ferrando
  4. Instituto de Neurociencias de Alicante, Alicante 03550, Spain.

    • Maria Cortina
    • , Esther Caparros
    •  & Maria Dominguez
  5. Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada.

    • Maria Ciofani
    •  & Juan Carlos Zúñiga-Pflücker
  6. Departments of Medicine and Endocrinology, Columbia University Medical Center, New York, New York 10032, USA.

    • Jean Buteau
  7. Pathology Department, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.

    • Sherrie L Perkins
    •  & Archana M Agarwal
  8. Hemato-Oncology Laboratory, Department of Pediatrics, University of Padua, Padua 35128, Italy.

    • Giuseppe Basso
  9. Department of Obstetrics and Gynecology, Tohoku University School of Medicine Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

    • Satoru Nagase

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Corresponding authors

Correspondence to Maria Dominguez or Adolfo A Ferrando.

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DOI

https://doi.org/10.1038/nm1636

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