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Los eventos multigenéticos contribuyen de forma colaborativa a la formación de células madre de la leucemia Pten-null
Wei Guo1, Joseph L Lasky, Chun-Ju Chang
1Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California 90095, USA.
Nature
|May 9, 2008
Resumen
La deleción de Pten en las células madre del ratón causa T-ALL mediante la activación de la beta-catenina y c-myc. Este estudio identifica los eventos moleculares clave en la transformación de células madre leucémicas.
Área de la Ciencia:
- Hematología Hematología.
- Oncología Oncología.
- Biología Molecular Biología Molecular
Sus antecedentes:
- Las células madre cancerosas (CSC) están implicadas en la tumorigénesis y la resistencia al tratamiento.
- La identificación de los CSC y sus vías de transformación es crucial en la biología del cáncer.
- La pérdida de pten está relacionada con varios tipos de cáncer, pero su papel en la iniciación de T-ALL requiere mayor aclaración.
Objetivo del estudio:
- Investigar el papel de la deleción de Pten en las células madre hematopoyéticas (HSC) en el desarrollo de T-ALL.
- Para identificar los eventos moleculares que impulsan la transformación de las células madre leucémicas (CEL).
- Explorar la contribución de las vías beta-catenin y c-myc en la T-ALL. con deficiencia de Pten.
Principales métodos:
- La deleción de Pten en HSCs de ratón.
- La citometría de flujo para identificar las poblaciones de LSC (c-Kit(mid) CD3(+) Lin(-)).
- Análisis de la expresión de beta-catenina y c-myc.
- Ablación genética condicional de la beta-catenina.
- Detección de las translocaciones cromosómicas (T(14;15)).
Principales resultados:
- La deleción de Pten en HSCs indujo trastorno mieloproliferativo y T-ALL.
- Los LSC se enriquecieron en el compartimento c-Kit (medio) CD3 (más) Lin (más) con un aumento de la beta-catenina.
- La activación de la vía de la beta-catenina contribuyó a la formación / expansión de la LSC.
- La translocación cromosómica T ((14;15) condujo a la sobreexpresión de c-myc en las LSC y los blastos leucémicos.
- La inactivación de Pten y la sobreexpresión de c-myc pueden sustituir funcionalmente a Notch1 en T-ALL.
Conclusiones:
- La pérdida de Pten coopera con la activación de la beta-catenina y la sobreexpresión de c-myc para impulsar T-ALL.
- Múltiples alteraciones genéticas contribuyen a la transformación de la LSC.
- Este modelo recapitula aspectos de la T-ALL humana y ofrece información sobre la biología del CSC.
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