title: Expression of CCL9/MIP-1gamma is repressed by BCR/ABL and its restoration suppresses in vivo leukemogenesis of 32D-BCR/ABL cells.
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.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: G
authors.initials: G
authors.lastname: Iotti
authors.forename: G
authors.initials: G
authors.lastname: Ferrari-Amorotti
authors.forename: C
authors.initials: C
authors.lastname: Rosafio
authors.forename: F
authors.initials: F
authors.lastname: Corradini
authors.forename: M R
authors.initials: MR
authors.lastname: Lidonnici
authors.forename: M
authors.initials: M
authors.lastname: Ronchetti
authors.forename: M
authors.initials: M
authors.lastname: Bardini
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Martinez
authors.forename: F
authors.initials: F
authors.lastname: Blasi
authors.forename: B
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D000818:Animals; D001549:Benzamides; D001854:Bone Marrow Cells / Q000473:pathology; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D015197:Carcinogenicity Tests; D049109:Cell Proliferation; D019742:Chemokines, CC; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D000068877:Imatinib Mesylate; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001549:Benzamides; D022763:CCAAT-Enhancer-Binding Protein-alpha; C095218:Ccl9 protein, mouse; D019742:Chemokines, CC; C000624101:Cux1 protein, mouse; D018398:Homeodomain Proteins; D019402:Macrophage Inflammatory Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012097:Repressor Proteins; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D048051:p38 Mitogen-Activated Protein Kinases