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

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 gamma-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.

• Authors: Teresa Palomero, Maria Luisa Sulis, Maria Cortina, Pedro J Real, Kelly Barnes, Maria Ciofani, Esther Caparros, Jean Buteau, Kristy Brown, Sherrie L Perkins, Govind Bhagat, Archana M Agarwal, Giuseppe Basso, Mireia Castillo, Satoru Nagase, Carlos Cordon-Cardo, Ramon Parsons, Juan Carlos Zúñiga-Pflücker, Maria Dominguez, Adolfo A Ferrando
• Journal: Nature medicine (Nat Med) Vol. 13 Issue 10 Pg. 1203-10 (Oct 2007) ISSN: 1078-8956 [Print] United States
• PMID: 17873882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Drosophila Proteins
• Receptor, Notch1
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, Drosophila
• PTEN protein, human

Topics

• Animals
• DNA Mutational Analysis
• Disease Models, Animal
• Drosophila (genetics, metabolism)
• Drosophila Proteins (genetics, metabolism)
• Female
• Gene Expression Regulation, Leukemic (genetics)
• Humans
• Leukemia, T-Cell (genetics, metabolism)
• Mice
• Models, Genetic
• Mutation
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Pregnancy
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Receptor, Notch1 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Transgenes