Publication Date:
2007-11-16
Description:
Activating mutations in NOTCH1 are common in T-cell lymphoblastic leukemias (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors (GSIs), which block NOTCH1 activation. However, enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by NOTCH1. Here, we identify the loss of the PTEN tumor suppressor gene and activation of the PI3K-AKT signaling pathway as critical factors that determine the resistance of T-ALL cells to inhibition of NOTCH1 signaling with GSIs. Mutational loss of PTEN is found in 17% of T-ALL cases and in the majority of T-ALL cell lines. Importantly, 8/8 T-ALL lines sensitive to NOTCH inhibition with GSIs retain wild type PTEN, while this tumor suppressor is lost in 8/8 GSI-resistant T-ALLs analyzed (P
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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