AML1-ETO mediates hematopoietic self-renewal and leukemogenesis through a COX/ß-catenin signaling pathway.
Blood
; 121(24): 4906-16, 2013 Jun 13.
Article
em En
| MEDLINE
| ID: mdl-23645839
ABSTRACT
Developing novel therapies that suppress self-renewal of leukemia stem cells may reduce the likelihood of relapses and extend long-term survival of patients with acute myelogenous leukemia (AML). AML1-ETO (AE) is an oncogene that plays an important role in inducing self-renewal of hematopoietic stem/progenitor cells (HSPCs), leading to the development of leukemia stem cells. Previously, using a zebrafish model of AE and a whole-organism chemical suppressor screen, we have discovered that AE induces specific hematopoietic phenotypes in embryonic zebrafish through a cyclooxygenase (COX)-2 and ß-catenin-dependent pathway. Here, we show that AE also induces expression of the Cox-2 gene and activates ß-catenin in mouse bone marrow cells. Inhibition of COX suppresses ß-catenin activation and serial replating of AE(+) mouse HSPCs. Genetic knockdown of ß-catenin also abrogates the clonogenic growth of AE(+) mouse HSPCs and human leukemia cells. In addition, treatment with nimesulide, a COX-2 selective inhibitor, dramatically suppresses xenograft tumor formation and inhibits in vivo progression of human leukemia cells. In summary, our data indicate an important role of a COX/ß-catenin-dependent signaling pathway in tumor initiation, growth, and self-renewal, and in providing the rationale for testing potential benefits from common COX inhibitors as a part of AML treatments.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
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Células-Tronco Hematopoéticas
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Leucemia Mieloide Aguda
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Transdução de Sinais
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Proteínas de Fusão Oncogênica
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Proliferação de Células
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Ciclo-Oxigenase 2
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Beta Catenina
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Subunidade alfa 2 de Fator de Ligação ao Core
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Blood
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos