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Apoptosis Induction by Retinoids in Eosinophilic Leukemia Cells: Implication of Retinoic Acid Receptor- Signaling in All-Trans-Retinoic Acid Hypersensitivity

¹ Institut National de la Santé et de la Recherche Médicale, UMR-S 718, Institut Universitaire d'Hématologie, University of Paris VII, Paris, France and ² National Medical Center, Department of Haematology and Stem Cell Transplantation, Budapest, Hungary

Requests for reprints: Béla Papp, Institut National de la Santé et de la Recherche Médicale, UMR-S 718, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, 16 rue de la Grange aux Belles, 75010 Paris, France. Phone: +33-1-53-72-40-10; Fax: +33-1-53-72-40-16; E-mail: bela.papp{at}chu-stlouis.fr.

Hypereosinophilic syndrome (HES) has recently been recognized as a clonal leukemic lesion, which is due to a specific oncogenic event that generates hyperactive platelet-derived growth factor receptor-–derived tyrosine kinase fusion proteins. In the present work, the effect of retinoids on the leukemic hypereosinophilia-derived EoL-1 cell line and on primary HES-derived cells has been investigated. We show that all-trans-retinoic acid (ATRA) inhibits eosinophil colony formation of HES-derived bone marrow cells and is a powerful inducer of apoptosis of the EoL-1 cell line. Apoptosis was shown in the nanomolar concentration range by phosphatidylserine externalization, proapoptotic shift of the Bcl-2/Bak ratio, drop in mitochondrial membrane potential, activation of caspases, and cellular morphology. Unlike in other ATRA-sensitive myeloid leukemia models, apoptosis was rapid and was not preceded by terminal cell differentiation. Use of isoform-selective synthetic retinoids indicated that retinoic acid receptor-–dependent signaling is sufficient to induce apoptosis of EoL-1 cells. Our work shows that the scope of ATRA-induced apoptosis of malignancies may be wider within the myeloid lineage than thought previously, that the EoL-1 cell line constitutes a new and unique model for the study of ATRA-induced cell death, and that ATRA may have potential for the management of clonal HES. (Cancer Res 2006; 66(12): 6336-44)

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