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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Palomero, T; Sulis, ML; Cortina, M; Real, PJ; Barnes, K; Ciofani, M; Caparros, E; Buteau, J; Brown, K; Perkins, SL; Bhagat, G; Agarwal, AM; Basso, G; Castillo, M; Nagase, S; Cordon-Cardo, C; Parsons, R; Zúñiga-Pflücker, JC; Dominguez, M; Ferrando, AA

Published Date

  • October 2007

Published In

Volume / Issue

  • 13 / 10

Start / End Page

  • 1203 - 1210

PubMed ID

  • 17873882

Pubmed Central ID

  • 17873882

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm1636

Language

  • eng

Conference Location

  • United States