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.
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.
['Brown|Sarah|S|', 'Hutchinson|Claire V|CV|', "Aspinall-O'Dea|Mark|M|", 'Whetton|Anthony D|AD|', 'Johnson|Suzanne M|SM|', 'Rees-Unwin|Karen|K|', 'Burthem|John|J|']
D008841:Actin Cytoskeleton D000199:Actins D048868:Adaptor Proteins, Signal Transducing D002454:Cell Differentiation D003713:Dendritic Cells D016044:Fusion Proteins, bcr-abl D015973:Gene Expression Regulation, Leukemic D006801:Humans D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive D009000:Monocytes D009687:Nuclear Proteins D061251:Primary Cell Culture D021381:Protein Transport D016315:Proto-Oncogene Proteins c-abl D051562:Proto-Oncogene Proteins c-bcr D015398:Signal Transduction
dendritic cells chronic myeloid leukaemia ABL