title: The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate.
abstract: The clinical progression of chronic myeloid leukemia (CML) from chronic phase to blast crisis is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes. This study was undertaken to investigate the influence of Bcr-Abl and of the small molecule Abl tyrosine-kinase inhibitor imatinib mesylate on granulocyte colony-stimulating factor (G-CSF)-induced neutrophilic differentiation. We show that differentiation of 32Dcl3 cells into mature granulocytes is accompanied by the increased expression of the antigens macrophage adhesion molecule-1 (Mac-1) and Gr-1, of the G-CSF receptor (G-CSFR), of myeloid transcription factors (CCAAT/enhancer-binding protein-alpha [C/EBPalpha], C/EBPepsilon, and PU.1), and of the cyclin-dependent kinase inhibitor p27(Kip1). In 32Dcl3 cells transfected with the bcr-abl gene (32D(Bcr-Abl)), G-CSF did not trigger either granulocytic differentiation or the up-regulation of C/EBPalpha, C/EBPepsilon, and the G-CSFR. This could be correlated to a defect in c-Myc down-regulation. In contrast, the up-regulation of PU.1 and p27(Kip1) by G-CSF was not affected by Bcr-Abl. Importantly, incubation of 32D(Bcr-Ablwt) cells with the kinase inhibitor imatinib mesylate prior to G-CSF stimulation completely neutralized the effects of Bcr-Abl on granulocytic differentiation and on C/EBPalpha and C/EBPepsilon expression. Taken together, the results suggest that the Bcr-Abl kinase induces a reversible block of the granulocytic differentiation program in myeloid cells by disturbing regulation of hematopoietic transcription factors such as C/EBPalpha and C/EBPepsilon.
authors.affiliation: Klinische Kooperationsgruppe Gentherapie, GSF-National Research Institute for Environment and Health, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Schuster
authors.forename: Karin
authors.initials: K
authors.lastname: Forster
authors.forename: Henning
authors.initials: H
authors.lastname: Dierks
authors.forename: Annika
authors.initials: A
authors.lastname: Elsasser
authors.forename: Gerhard
authors.initials: G
authors.lastname: Behre
authors.forename: Nicola
authors.initials: N
authors.lastname: Simon
authors.forename: Susanne
authors.initials: S
authors.lastname: Danhauser-Riedl
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D022762:CCAAT-Enhancer-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D004791:Enzyme Inhibitors; D016044:Fusion Proteins, bcr-abl; D016179:Granulocyte Colony-Stimulating Factor; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C436291:CDKN1B protein, human; C493957:Cdkn1a protein, mouse