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Blood, 1 March 2007, Vol. 109, No. 5, pp. 2121-2129.
Prepublished online as a Blood First Edition Paper on October 31, 2006; DOI 10.1182/blood-2006-05-024679.
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Submitted May 22, 2006
Accepted October 15, 2006
MEK blockade converts AML differentiating response to retinoids into extensive apoptosis
Michele Milella*, Marina Konopleva, Cristina M Precupanu, Yoko Tabe, Maria Rosaria Ricciardi, Chiara Gregorj, Steven J Collins, Bing Z Carter, Carmen D'Angelo, Maria Teresa Petrucci, Robin Foa, Francesco Cognetti, Agostino Tafuri, and Michael Andreeff
Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy
Section of Molecular Hematology & Therapy, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States
Dept of Biotecnologie Cellulari ed Ematologia, University of Rome, Rome, Italy
Molecular Mecidine Program, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Laboratory of Experimental Preclinical Chemotherapy, Regina Elena National Cancer Institute, Rome, Italy
* Corresponding author; email: milella{at}ifo.it.
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 AML and APL cells with constitutive ERK activation. This pro-apoptotic 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 "post-maturation" apoptosis induced by retinoids alone. Finally, we identify disruption of Bcl-2-dependent mitochondrial homeostasis as a possible point of convergence for the pro-apoptotic synergism observed with retinoids and MEK inhibitors. Taken together, these results indicate that combined retinoid treatment and MEK blockade exerts powerful anti-leukemic effects and could be developed into a novel therapeutic strategy for both AML and APL.
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