Functional crosstalk between Bmi1 and MLL/Hoxa9 axis in establishment of normal hematopoietic and leukemic stem cells.
Cell Stem Cell
; 8(6): 649-62, 2011 Jun 03.
Article
em En
| MEDLINE
| ID: mdl-21624810
ABSTRACT
Bmi1 is required for efficient self-renewal of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). In this study, we investigated whether leukemia-associated fusion proteins, which differ in their ability to activate Hox expression, could initiate leukemia in the absence of Bmi1. AML1-ETO and PLZF-RARα, which do not activate Hox, triggered senescence in Bmi1(-/-) cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9, readily transformed Bmi1(-/-) cells. MLL-AF9 could not initiate leukemia in Bmi1(-/-)Hoxa9(-/-) mice, which have further compromised HSC functions. But either gene could restore the ability of MLL-AF9 to establish LSCs in the double null background. As reported for Bmi1, Hoxa9 regulates expression of p16(Ink4a)/p19(ARF) locus and could overcome senescence induced by AML1-ETO. Together, these results reveal an important functional interplay between MLL/Hox and Bmi1 in regulating cellular senescence for LSC development, suggesting that a synergistic targeting of both molecules is required to eradicate a broader spectrum of LSCs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
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Células-Tronco Neoplásicas
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Células-Tronco Hematopoéticas
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Proteínas Nucleares
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Proteínas de Fusão Oncogênica
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Proteínas Proto-Oncogênicas
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Proteínas de Homeodomínio
Limite:
Animals
Idioma:
En
Revista:
Cell Stem Cell
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Reino Unido
País de publicação:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA