MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia.
Blood
; 125(16): 2544-52, 2015 Apr 16.
Article
en En
| MEDLINE
| ID: mdl-25740828
ABSTRACT
Leukemias with MLL translocations are often found in infants and are associated with poor outcomes. The pathogenesis of MLL-fusion leukemias has been linked to upregulation of HOX/MEIS1 genes. The functions of the Hox/Meis1 complex in leukemia, however, remain elusive. Here, we used inducible Meis1-knockout mice coupled with MLL-AF9 knockin mice to decipher the mechanistic role of Meis1 in established MLL leukemia. We demonstrate that Meis1 is essential for maintenance of established leukemia. In addition, in both the murine model and human leukemia cells, we found that Meis1 loss led to increased oxidative stress, oxygen flux, and apoptosis. Gene expression and chromatin immunoprecipitation studies revealed hepatic leukemia factor (HLF) as a target gene of Meis1. Hypoxia or HLF expression reversed the oxidative stress, rescuing leukemia development in Meis1-deficient cells. Thus, the leukemia-promoting properties of Meis1 are at least partly mediated by a low-oxidative state, aided by HLF. These results suggest that stimulants of oxidative metabolism could have therapeutic potential in leukemia treatment.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Leucemia
/
Proteínas de Fusión Oncogénica
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Estrés Oxidativo
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Proteínas de Homeodominio
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Factores de Transcripción con Cremalleras de Leucina de Carácter Básico
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Proteína de la Leucemia Mieloide-Linfoide
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Proteínas de Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Año:
2015
Tipo del documento:
Article