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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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NEOPLASIA

MEK blockade converts AML differentiating response to retinoids into extensive apoptosis

Michele Milella1, Marina Konopleva2, Cristina M. Precupanu1, Yoko Tabe2, Maria Rosaria Ricciardi2,3, Chiara Gregorj3, Steven J. Collins4, Bing Z. Carter2, Carmen D'Angelo5, Maria Teresa Petrucci3, Robin Foà3, Francesco Cognetti1, Agostino Tafuri3, and Michael Andreeff2

1 Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy; 2 Section of Molecular Hematology and Therapy, University of Texas M. D. Anderson Cancer Center, Houston; 3 Department of Cellular Biotechnology and Hematology, University of Rome "La Sapienza," Rome, Italy; 4 Molecular Medicine Program, Fred Hutchinson Cancer Research Center, Seattle, WA; 5 Laboratory of Experimental Preclinical Chemotherapy, Regina Elena National Cancer Institute, Rome, Italy

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.


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