Induction of differentiation by IL-6-type cytokines is impaired in myeloid leukaemia cells unable to activate Stat5a.
The block of differentiation in myeloid leukaemia can be overcome by treatment with a variety of agents including cytokines. Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) induce macrophage differentiation and growth arrest through activation of the Janus kinase (Jak)/signal transducers and activators of transcription (Stat) signal pathway in murine M1 myeloid leukaemia cells. Treatment of various other myeloid leukaemia lines with LIF or IL-6 did not lead to induction of differentiation. Several defects in the cytokine triggered Jak/Stat signal pathway were striking in these lines. They expressed a decreased or undetectable amount of at least one of the components of the specific cytokine receptor complexes. Three lines contained a constitutively activated Jak/Stat signal cascade and in two of them, lines C and BMC-63, this cascade was inducible by treatment with IL-6, despite of a very low density of IL-6-receptors. Apart from the cytokine receptors, additional components of the Jak/Stat signal cascade were altered in these lines. Expression and activation of the transcription factor Stat5a and the tyrosine kinase Jak2 were markedly decreased compared to M1 cells, suggesting a role of activated Stat5a in the induction of differentiation. These results demonstrate a direct correlation between alterations in the Jak/Stat signal pathway and the inability to differentiate after cytokine treatment of myeloid leukaemia cells.
Piekorz
R P
RP
Institute for Microbiology, Biochemistry and Genetics, University of Erlangen-Nürnberg, Germany.
Hocke
G M
GM
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006131:Growth Inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D053614:Janus Kinase 2; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D008894:Milk Proteins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D018121:Receptors, Cytokine / Q000235:genetics; D019947:Receptors, Interleukin-6 / Q000235:genetics; D053606:Receptors, OSM-LIF; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008070:Lipopolysaccharides; D008222:Lymphokines; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; D053606:Receptors, OSM-LIF; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D014212:Tretinoin; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2