title: Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL.
abstract: Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.
authors.affiliation: Department of Microbiology and Immunology, Division of Hematology and Oncology, University of Miami School of Medicine, Miami, FL 33136, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Lindner
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Kharfan-Dabaja
authors.forename: Ernesto
authors.initials: E
authors.lastname: Ayala
authors.forename: Despina
authors.initials: D
authors.lastname: Kolonias
authors.forename: Louise M
authors.initials: LM
authors.lastname: Carlson
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Beazer-Barclay
authors.forename: Uwe
authors.initials: U
authors.lastname: Scherf
authors.forename: James H
authors.initials: JH
authors.lastname: Hnatyszyn
authors.forename: Kelvin P
authors.initials: KP
authors.lastname: Lee
mesh_terms: D001752:Blast Crisis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000201:enzymology / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D016313:Genes, abl / Q000276:immunology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051562:Proto-Oncogene Proteins c-bcr; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium