A PI3K p110ß-Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis.
Nat Commun
; 6: 8501, 2015 Oct 07.
Article
em En
| MEDLINE
| ID: mdl-26442967
ABSTRACT
The tumour suppressor PTEN, which antagonizes PI3K signalling, is frequently inactivated in haematologic malignancies. In mice, deletion of PTEN in haematopoietic stem cells (HSCs) causes perturbed haematopoiesis, myeloproliferative neoplasia (MPN) and leukaemia. Although the roles of the PI3K isoforms have been studied in PTEN-deficient tumours, their individual roles in PTEN-deficient HSCs are unknown. Here we show that when we delete PTEN in HSCs using the Mx1-Cre system, p110ß ablation prevents MPN, improves HSC function and suppresses leukaemia initiation. Pharmacologic inhibition of p110ß in PTEN-deficient mice recapitulates these genetic findings, but suggests involvement of both Akt-dependent and -independent pathways. Further investigation reveals that a p110ß-Rac signalling loop plays a critical role in PTEN-deficient HSCs. Together, these data suggest that myeloid neoplasia driven by PTEN loss is dependent on p110ß via p110ß-Rac-positive-feedback loop, and that disruption of this loop may offer a new and effective therapeutic strategy for PTEN-deficient leukaemia.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Leucemia
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PTEN Fosfo-Hidrolase
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Classe I de Fosfatidilinositol 3-Quinases
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Hematopoese
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Transtornos Mieloproliferativos
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article