MEK blockade converts AML differentiating response to retinoids into extensive apoptosis.
The aberrant function of transcription factors and/or kinase-based signaling pathways that regulate the ability of hematopoietic cells to proliferate, differentiate, and escape apoptosis accounts for the leukemic transformation of myeloid progenitors. Here, we demonstrate that simultaneous retinoid receptor ligation and blockade of the MEK/ERK signaling module, using the small-molecule inhibitor CI-1040, result in a strikingly synergistic induction of apoptosis in both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells with constitutive ERK activation. This proapoptotic synergism requires functional RAR and RXR retinoid receptors, as demonstrated using RAR- and RXR-selective ligands and RAR-defective cells. In the presence of MEK inhibitors, however, retinoid-induced chromatin remodeling, target-gene transcription, and granulocytic differentiation are strikingly inhibited and apoptosis induction becomes independent of death-inducing ligand/receptor pairs; this suggests that apoptosis induction by combined retinoids and MEK inhibitors is entirely distinct from the classical "postmaturation" apoptosis induced by retinoids alone. Finally, we identify disruption of Bcl-2-dependent mitochondrial homeostasis as a possible point of convergence for the proapoptotic synergism observed with retinoids and MEK inhibitors. Taken together, these results indicate that combined retinoid treatment and MEK blockade exert powerful antileukemic effects and could be developed into a novel therapeutic strategy for both AML and APL.
Milella
Michele
M
Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy. milella@ifo.it
Konopleva
Marina
M
Precupanu
Cristina M
CM
Tabe
Yoko
Y
Ricciardi
Maria Rosaria
MR
Gregorj
Chiara
C
Collins
Steven J
SJ
Carter
Bing Z
BZ
D'Angelo
Carmen
C
Petrucci
Maria Teresa
MT
Foà
Robin
R
Cognetti
Francesco
F
Tafuri
Agostino
A
Andreeff
Michael
M
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases