title: Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration.
abstract: Chronic myeloid leukemia (CML) is characterized by expression of the BCR-ABL fusion gene that encodes a 210-kDa protein, which is a constitutively active tyrosine kinase. At least 70% of the oncoprotein is localized to the cytoskeleton, and several of the most prominent tyrosine kinase substrates for p210(BCR-ABL) are cytoskeletal proteins. Dendritic cells (DCs) are bone marrow-derived antigen-presenting cells responsible for the initiation of immune responses. In CML patients, up to 98% of myeloid DCs generated from peripheral blood mononuclear cells are BCR-ABL positive. In this study we have compared the morphology and behavior of myeloid DCs derived from CML patients with control DCs from healthy individuals. We show that the actin cytoskeleton and shape of CML-DCs of myeloid origin adherent to fibronectin differ significantly from those of normal DCs. CML-DCs are also defective in processing and presentation of exogenous antigens such as tetanus toxoid. The antigen-processing defect may be a consequence of the reduced capacity of CML-DCs to capture antigen via macropinocytosis or via mannose receptors when compared with DCs generated from healthy individuals. Furthermore, chemokine-induced migration of CML-DCs in vitro was significantly reduced. These observations cannot be explained by a difference in the maturation status of CML and normal DCs, because phenotypic analysis by flow cytometry showed a similar surface expression of maturation makers. Taken together, these results suggest that the defects in antigen processing and migration we have observed in CML-DCs may be related to underlying cytoskeletal changes induced by the p210(BCR-ABL) fusion protein.
authors.affiliation: Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College at Hammersmith Hospital, London, United Kingdom.
authors.forename: Rong
authors.initials: R
authors.lastname: Dong
authors.forename: Kate
authors.initials: K
authors.lastname: Cwynarski
authors.forename: Alan
authors.initials: A
authors.lastname: Entwistle
authors.forename: Federica
authors.initials: F
authors.lastname: Marelli-Berg
authors.forename: Francesco
authors.initials: F
authors.lastname: Dazzi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: John M
authors.initials: JM
authors.lastname: Goldman
authors.forename: Junia V
authors.initials: JV
authors.lastname: Melo
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lechler
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bellantuono
authors.forename: Anne
authors.initials: A
authors.lastname: Ridley
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure*; D000199:Actins / Q000032:analysis*; D000293:Adolescent; D000328:Adult; D017951:Antigen Presentation; D002448:Cell Adhesion; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002633:Chemotaxis; D003599:Cytoskeleton / Q000648:ultrastructure*; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology*; D004705:Endocytosis; D005353:Fibronectins; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D037181:Lectins, C-Type; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D018613:Microscopy, Confocal; D009000:Monocytes / Q000187:drug effects; D009363:Neoplasm Proteins / Q000502:physiology; D010873:Pinocytosis; D011956:Receptors, Cell Surface / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013745:Tetanus Toxoid / Q000276:immunology
chemical_list: D000199:Actins; D005353:Fibronectins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface; D013745:Tetanus Toxoid