MEK inhibition induces caspases activation, differentiation blockade and PML/RARalpha degradation in acute promyelocytic leukaemia.
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 alpha (PML/RARalpha) fusion protein and a cell differentiation blockade at the promyelocytic stage. PML/RARalpha is directly targeted by all-trans-retinoic acid (ATRA), which degrades the oncoprotein and induces complete remission of malignancies. The aberrant function of PML/RARalpha, 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/RARalpha 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/RARalpha, and attenuation of the cell differentiation induction. To our knowledge, this is the first report to show that PML/RARalpha was suppressed by MEK/ERK inhibition, through a mechanism dependent on caspase activation. ATRA co-operated with MEK inhibitor to increase degradation of PML/RARalpha 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.
Barbarroja
Nuria
N
Unidad de Investigación, Hospital Universitario Reina Sofía, Córdoba, Spain. nuria.barbarroja.exts@juntadeandalucia.es
Siendones
Emilio
E
Torres
Luis Arístides
LA
Luque
Maria Jose
MJ
Martinez
Julio Manuel
JM
Dorado
Gabriel
G
Velasco
Francisco
F
Torres
Antonio
A
López-Pedrera
Chary
C
D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases