1. 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.
- Author
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Brown S, Hutchinson CV, Aspinall-O'Dea M, Whetton AD, Johnson SM, Rees-Unwin K, and Burthem J
- Subjects
- Actin Cytoskeleton genetics, Actin Cytoskeleton metabolism, Actin Cytoskeleton ultrastructure, Actins genetics, Actins metabolism, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Cell Differentiation, Dendritic Cells pathology, Dendritic Cells ultrastructure, Fusion Proteins, bcr-abl metabolism, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Monocytes metabolism, Monocytes pathology, Nuclear Proteins genetics, Nuclear Proteins metabolism, Primary Cell Culture, Protein Transport, Proto-Oncogene Proteins c-abl metabolism, Proto-Oncogene Proteins c-bcr genetics, Proto-Oncogene Proteins c-bcr metabolism, Dendritic Cells metabolism, Fusion Proteins, bcr-abl genetics, Gene Expression Regulation, Leukemic, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Proto-Oncogene Proteins c-abl genetics, Signal Transduction genetics
- Abstract
Objectives: 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., Results and 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., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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