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MEK inhibition induces caspases activation, differentiation blockade and PML/RARα degradation in acute promyelocytic leukaemia
Author(s) -
Barbarroja Nuria,
Siendones Emilio,
Torres Luis Arístides,
Luque Mª Jose,
Martinez Julio Manuel,
Dorado Gabriel,
Velasco Francisco,
Torres Antonio,
LópezPedrera Chary
Publication year - 2008
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2008.07154.x
Subject(s) - mapk/erk pathway , acute promyelocytic leukemia , retinoic acid , cancer research , mek inhibitor , tretinoin , microbiology and biotechnology , kinase , biology , cell culture , genetics
Summary 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.