Abstract
Transformation of hematopoietic cells by the BCR/ABL oncogene is caused by perturbation of signal transduction pathways leading to altered patterns of gene expression and activity. By oligonucleotide microarray hybridization of polysomal RNA of untreated and STI571-treated 32D-BCR/ABL cells, we identified the beta-chemokine CCL9 as a gene regulated by BCR/ABL in a tyrosine kinase-dependent manner. BCR/ABL repressed CCL9 expression at the transcriptional level by mechanisms involving suppression of p38 MAP kinase, and modulation of the activity of CDP/cut and C/EBPalpha, two transcription regulators of myeloid differentiation. However, repression of C/EBP-dependent transcription did not prevent the induction of CCL9 expression by STI571, suggesting that C/EBPalpha is involved in maintaining rather than in inducing CCL9 expression. Restoration of CCL9 expression in 32D-BCR/ABL cells had no effect on the in vitro proliferation of these cells, but reduced their leukemogenic potential in vivo, possibly by recruitment of CD3-positive immune cells. Together, these findings suggest that downregulation of chemokine expression may be involved in BCR/ABL-dependent leukemogenesis by altering the relationship between transformed cells and the microenvironment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides
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Bone Marrow Cells / pathology
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CCAAT-Enhancer-Binding Protein-alpha / genetics
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CCAAT-Enhancer-Binding Protein-alpha / metabolism
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Carcinogenicity Tests
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Cell Proliferation
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Chemokines, CC
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Down-Regulation
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism*
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Gene Expression Regulation, Leukemic
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Imatinib Mesylate
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Leukemia, Myeloid / genetics*
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Leukemia, Myeloid / pathology
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Macrophage Inflammatory Proteins / genetics
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Macrophage Inflammatory Proteins / metabolism*
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Mice
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Mice, Inbred C3H
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Mice, SCID
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Piperazines / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / pharmacology
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Tumor Cells, Cultured
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Benzamides
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CCAAT-Enhancer-Binding Protein-alpha
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Ccl9 protein, mouse
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Chemokines, CC
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Cux1 protein, mouse
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Homeodomain Proteins
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Macrophage Inflammatory Proteins
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Nuclear Proteins
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Repressor Proteins
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Imatinib Mesylate
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Fusion Proteins, bcr-abl
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p38 Mitogen-Activated Protein Kinases