Notch signaling in acute promyelocytic leukemia.
Leukemia
; 27(7): 1548-1557, 2013 Jul.
Article
em En
| MEDLINE
| ID: mdl-23455394
ABSTRACT
Acute promyelocytic leukemia (APL) is initiated by the PML-RARA (PR) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 (JAG1). In this study, we used a series of bioinformatic, in vitro, and in vivo assays to assess the role of Notch signaling in human APL samples, and in a PML-RARA knock-in mouse model of APL (Ctsg-PML-RARA). We identified a Notch expression signature in both human primary APL cells and in Kit+Lin-Sca1+ cells from pre-leukemic Ctsg-PML-RARA mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic Ctsg-PML-RARA mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth in vitro when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth in vivo in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia Promielocítica Aguda
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Transdução de Sinais
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Receptor Notch1
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article