The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia.
Haematologica
; 101(9): 1010-7, 2016 09.
Article
em En
| MEDLINE
| ID: mdl-27582570
ABSTRACT
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that inactivate PTEN together with other molecular mechanisms that activate AKT and contribute to T-cell leukemogenesis. In addition, we discuss how Pten mutations in mouse models affect the efficacy of gamma-secretase inhibitors to block NOTCH1 signaling through activation of AKT. Based on these models and on observations in primary diagnostic samples from patients with T-cell acute lymphoblastic leukemia, we speculate that PTEN-deficient cells employ an intrinsic homeostatic mechanism in which PI3K-AKT signaling is dampened over time. As a result of this reduced PI3K-AKT signaling, the level of AKT activation may be insufficient to compensate for NOTCH1 inhibition, resulting in responsiveness to gamma-secretase inhibitors. On the other hand, de novo acquired PTEN-inactivating events in NOTCH1-dependent leukemia could result in temporary, strong activation of PI3K-AKT signaling, increased glycolysis and glutaminolysis, and consequently gamma-secretase inhibitor resistance. Due to the central role of PTEN-AKT signaling and in the resistance to NOTCH1 inhibition, AKT inhibitors may be a promising addition to current treatment protocols for T-cell acute lymphoblastic leukemia.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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PTEN Fosfo-Hidrolase
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Proteínas Proto-Oncogênicas c-akt
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Receptor Notch1
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
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Terapia de Alvo Molecular
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Antineoplásicos
Tipo de estudo:
Etiology_studies
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Guideline
Limite:
Animals
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Humans
Idioma:
En
Revista:
Haematologica
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Holanda