Article abstract
Nature Medicine 13, 1203 - 1210 (2007)
Published online: 16 September 2007 | doi:10.1038/nm1636
Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia
Teresa Palomero1,2, Maria Luisa Sulis1,3,10, Maria Cortina4,10, Pedro J Real1, Kelly Barnes1, Maria Ciofani5, Esther Caparros4, Jean Buteau6, Kristy Brown2, Sherrie L Perkins7, Govind Bhagat2, Archana M Agarwal7, Giuseppe Basso8, Mireia Castillo2, Satoru Nagase9, Carlos Cordon-Cardo2, Ramon Parsons1, Juan Carlos Zúñiga-Pflücker5, Maria Dominguez4 & Adolfo A Ferrando1,2,3
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 
-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.
- Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
- Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA.
- Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
- Instituto de Neurociencias de Alicante, Alicante 03550, Spain.
- Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada.
- Departments of Medicine and Endocrinology, Columbia University Medical Center, New York, New York 10032, USA.
- Pathology Department, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.
- Hemato-Oncology Laboratory, Department of Pediatrics, University of Padua, Padua 35128, Italy.
- Department of Obstetrics and Gynecology, Tohoku University School of Medicine Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
- These authors contributed equally to this work.
Correspondence to: Adolfo A Ferrando1,2,3 e-mail: af2196@columbia.edu
Correspondence to: Maria Dominguez4 e-mail: m.dominguez@umh.es
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