title: Monocyte-derived dendritic cells from chronic myeloid leukaemia have abnormal maturation and cytoskeletal function that is associated with defective localisation and signalling by normal ABL1 protein.
abstract: OBJECTIVE
  Mature dendritic cells (DCs) may be derived from the BCR/ABL1 expressing monocytes in chronic myeloid leukaemia. These cells have potential therapeutic applications, but are recognised to have defective function. In normal DCs, activation and maturation depend on ABL1 dependent signals. We therefore tested the hypothesis that in the DCs of chronic myeloid leukaemia, the presence of the BCR/ABL1 molecule disrupts normal ABL1 signal pathways, and contributes to the observed functional defects of the cells.
  
  
  METHODS
  We employed in vitro culture of clinical samples, combining microscopic and biochemical techniques with a phosphoproteomic approach to compare and characterise DCs from normal individuals and chronic myeloid leukaemia patients.
  
  
  CONCLUSIONS
  We identified an altered intracellular localisation for ABL1 within DCs derived from the monocytes of chronic myeloid leukaemia. The protein was found in the perinuclear region co-distributed with the adapter-protein CRKL and the BCR/ABL1 protein. This altered distribution was associated with defective generation of ABL1-dependent maturation signals, and a dislocation of ABL1 from the F-actin cytoskeleton. We suggest that abnormal ABL1-dependent signals contribute to the recognised functional defects affecting chronic myeloid leukaemia DCs.
authors.affiliation: Pharmacy Department, University of Wolverhampton, Wolverhampton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Brown
authors.forename: Claire V
authors.initials: CV
authors.lastname: Hutchinson
authors.forename: Mark
authors.initials: M
authors.lastname: Aspinall-O'Dea
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Whetton
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Johnson
authors.forename: Karen
authors.initials: K
authors.lastname: Rees-Unwin
authors.forename: John
authors.initials: J
authors.lastname: Burthem
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000199:Actins / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D021381:Protein Transport; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics* / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C581634:BCR-ABL1 fusion protein, human; C082869:CRKL protein; D009687:Nuclear Proteins; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr
keywords: ABL; chronic myeloid leukaemia; dendritic cells