Leukemia initiated by PMLRARalpha: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable.
Blood
; 95(5): 1541-50, 2000 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-10688806
ABSTRACT
The most common chromosomal translocation in acute promyelocytic leukemia (APL), t15;17(q22;q21), creates PMLRARalpha and RARalphaPML fusion genes. We previously developed a mouse model of APL by expressing PMLRARalpha in murine myeloid cells. In order to examine the mechanisms by which PMLRARalpha can initiate leukemia, we have now generated transgenic mice expressing PMLRARalpham4 and RARalpham4, proteins that are unable to activate transcription in response to retinoic acid. PMLRARalpham4 transgenic mice developed myeloid leukemia, demonstrating that transcriptional activation by PMLRARalpha is not required for leukemic transformation. The characteristics of the leukemias arising in the PMLRARalpham4 transgenic mice varied from those previously observed in our PMLRARalpha transgenic mice, indicating that ligand responsiveness may influence the phenotype of the leukemic cells. The leukemias that arose in PMLRARalpham4 transgenic mice did not differentiate in response to retinoic acid therapy. This result supports the hypothesis that a major therapeutic effect of retinoic acid is mediated directly through the PMLRARalpha protein. However, a variable effect on survival suggested that this agent may be of some benefit in APL even when leukemic cells are resistant to its differentiative effects. Transgenic mice expressing high levels of RARalpham4 have not developed leukemia, providing evidence that the PML domain of PMLRARalpha plays a specific and critical role in the pathogenesis of APL. (Blood. 2000;951541-1550)
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Bases de dados:
MEDLINE
Assunto principal:
Tretinoína
/
Leucemia Promielocítica Aguda
/
Leucemia Experimental
/
Regulação Leucêmica da Expressão Gênica
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Proteínas de Fusão Oncogênica
/
Ativação Transcricional
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Transformação Celular Neoplásica
/
Proteínas de Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Blood
Ano de publicação:
2000
Tipo de documento:
Article
País de afiliação:
Estados Unidos