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Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration
Rong Dong1, Kate Cwynarski, Alan Entwistle
1Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College at Hammersmith Hospital, London, United Kingdom.
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.
Insights
Chronic myeloid leukemia (CML) disrupts dendritic cell (DC) function, impairing antigen presentation and migration. These defects in BCR-ABL positive myeloid DCs are linked to cytoskeletal alterations.
Area of Science:
- Immunology
- Hematology
- Cell Biology
Background:
- Chronic myeloid leukemia (CML) is driven by the BCR-ABL fusion gene, producing a tyrosine kinase.
- Dendritic cells (DCs) are crucial antigen-presenting cells for initiating immune responses.
- BCR-ABL positive myeloid DCs are prevalent in CML patients.
Purpose of the Study:
- To compare the morphology and function of myeloid DCs from CML patients versus healthy individuals.
- To investigate the impact of BCR-ABL on DC cytoskeletal structure, antigen processing, and migration.
Main Methods:
- Comparative analysis of myeloid DCs from CML patients and healthy donors.
- Assessment of actin cytoskeleton and cell shape.
- Evaluation of antigen processing and presentation (e.g., tetanus toxoid).
- Analysis of antigen capture via macropinocytosis and mannose receptors.
- Measurement of chemokine-induced DC migration in vitro.
- Phenotypic analysis using flow cytometry for maturation markers.
Main Results:
- CML-derived DCs exhibit altered actin cytoskeleton and cell shape compared to normal DCs.
- CML-DCs show defects in processing and presenting exogenous antigens.
- Reduced antigen capture capacity via macropinocytosis and mannose receptors in CML-DCs.
- Significantly impaired chemokine-induced migration of CML-DCs in vitro.
- No significant difference in maturation marker expression between CML and normal DCs.
Conclusions:
- BCR-ABL positive myeloid DCs in CML patients have functional deficits in antigen processing and migration.
- These defects are associated with underlying cytoskeletal changes induced by the BCR-ABL fusion protein.
- The findings highlight potential immune dysregulation in CML patients due to DC dysfunction.