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Título: | MEK inhibition induces caspases activation, differentiation blockade and PML/RARα degradation in acute promyelocytic leukaemia |
Autor: | Barbarroja, Nuria; Siendones, Emilio CSIC; Arístides Torres, Luis; Luque, Mª Jose; Martinez, Julio Manuel; Dorado, Gabriel; Velasco, Francisco; Torres, Antonio; López-Pedrera, Chary | Palabras clave: | Acute promyelocytic leukemia Promyelocytic leukaemia/retinoic acid receptor α MEK/ERK All-trans-retinoic acid |
Fecha de publicación: | 2008 | Editor: | Blackwell Publishing | Citación: | British Journal of Haematology 142(1): 27-35 (2008) | Resumen: | The hallmark of acute promyelocytic leukaemia (APL) is the reciprocal translocation t(15;17), which leads to the expression of the promyelocytic leukaemia/retinoic acid receptor α (PML/RARα) fusion protein and a cell differentiation blockade at the promyelocytic stage. PML/RARα is directly targeted by all-trans-retinoic acid (ATRA), which degrades the oncoprotein and induces complete remission of malignancies. The aberrant function of PML/RARα, together with the constitutive activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK/ERK) signalling pathway, regulates the ability of haematopoietic cells to proliferate, differentiate, and escape from apoptotic episodes. The role of the MEK/ERK pathway in PML/RARα expression, differentiation, proliferation and apoptosis in APL cells was analysed using specific MEK inhibitors. The blockade of MEK/ERK pathway resulted in caspase-dependent degradation of PML/RARα, and attenuation of the cell differentiation induction. To our knowledge, this is the first report to show that PML/RARα was suppressed by MEK/ERK inhibition, through a mechanism dependent on caspase activation. ATRA co-operated with MEK inhibitor to increase degradation of PML/RARα and exhibited a convergence point in caspase activation with MEK inhibitors. Taken together, our data suggest a new role of MEK/ERK pathway in the pathogenesis of APL, thus supporting the use of MEK/ERK inhibitors as an efficient therapeutic strategy for this haematological malignancy. | Versión del editor: | http://dx.doi.org/10.1111/j.1365-2141.2008.07154.x | URI: | http://hdl.handle.net/10261/198812 | DOI: | 10.1111/j.1365-2141.2008.07154.x | Identificadores: | doi: 10.1111/j.1365-2141.2008.07154.x issn: 0007-1048 e-issn: 1365-2141 |
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