title: Apoptosis induction by retinoids in eosinophilic leukemia cells: implication of retinoic acid receptor-alpha signaling in all-trans-retinoic acid hypersensitivity.
abstract: 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-alpha-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-alpha-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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR-S 718, Institut Universitaire d'Hématologie, University of Paris VII, Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Robert
authors.forename: Laurent
authors.initials: L
authors.lastname: Delva
authors.forename: Nicole
authors.initials: N
authors.lastname: Balitrand
authors.forename: Sarolta
authors.initials: S
authors.lastname: Nahajevszky
authors.forename: Tamàs
authors.initials: T
authors.lastname: Masszi
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.forename: Béla
authors.initials: B
authors.lastname: Papp
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004342:Drug Hypersensitivity / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018922:HL-60 Cells; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D014212:Tretinoin / Q000494:pharmacology*; D039221:mRNA Cleavage and Polyadenylation Factors / Q000096:biosynthesis
chemical_list: C479818:FIP1L1 protein, human; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D039221:mRNA Cleavage and Polyadenylation Factors; D014212:Tretinoin