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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(s) -
Brown Sarah,
Hutchinson Claire V.,
AspinallO'Dea Mark,
Whetton Anthony D.,
Johnson Suzanne M.,
ReesUnwin Karen,
Burthem John
Publication year - 2014
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12306
Subject(s) - myeloid leukemia , abl , microbiology and biotechnology , biology , myeloid , signal transducing adaptor protein , monocyte , immunology , cancer research , signal transduction , tyrosine kinase
Abstract Objectives Mature dendritic cells ( DC s) 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 DC s, activation and maturation depend on ABL1 dependent signals. We therefore tested the hypothesis that in the DC s 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 DC s from normal individuals and chronic myeloid leukaemia patients. Results and conclusions We identified an altered intracellular localisation for ABL1 within DC s 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 DC s.