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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-06-1841.
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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3560-3567
IMMUNOBIOLOGY
Dendritic cells from CML patients have altered actin
organization, reduced antigen processing, and impaired
migration
Rong Dong,
Kate Cwynarski,
Alan Entwistle,
Federica Marelli-Berg,
Francesco Dazzi,
Elizabeth Simpson,
John M. Goldman,
Junia V. Melo,
Robert I. Lechler,
Ilaria Bellantuono,
Anne Ridley, and
Giovanna Lombardi
From the Department of Immunology, Division of
Medicine, and Department of Haematology, Division of Investigative
Science, Faculty of Medicine, Imperial College at Hammersmith Hospital,
London; Transplantation Biology Group, Medical Research
Council (MRC) Clinical Sciences Centre (CSC), Imperial College at
Hammersmith Hospital, London; and The Ludwig Institute for
Cancer Research and Department of Biochemistry and Molecular Biology,
University College, London, United Kingdom.
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 p210BCR-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 tetanous 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 p210BCR-ABL
fusion protein.
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