A myeloid tumor suppressor role for NOL3.
J Exp Med
; 214(3): 753-771, 2017 03 06.
Article
em En
| MEDLINE
| ID: mdl-28232469
ABSTRACT
Despite the identification of several oncogenic driver mutations leading to constitutive JAK-STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3-/- MPN mice harbor an expanded Thy1+LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by Nol3-/--induced JAK-STAT activation and downstream activation of cyclin-dependent kinase 6 (Cdk6) and MycNol3-/- MPN Thy1+LSK cells share significant molecular similarities with primary CD34+ cells from PMF patients. NOL3 levels are decreased in CD34+ cells from PMF patients, and the NOL3 locus is deleted in a subset of patients with myeloid malignancies. Our results reveal a novel genetic PMF-like mouse model and identify a tumor suppressor role for NOL3 in the pathogenesis of myeloid malignancies.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Supressoras de Tumor
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Proteínas Reguladoras de Apoptose
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Proteínas Musculares
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article