INDUCTION OF DIFFERENTIATION BY IL-6-TYPE CYTOKINES IS IMPAIRED IN MYELOID-LEUKEMIA CELLS UNABLE TO ACTIVATE STAT5A

The block of differentiation in myeloid leukaemia can be overcome by t reatment with a variety of agents including cytokines, Interleukin 6 ( IL-6) and leukaemia inhibitory factor (LIF) induce macrophage differen tiation and growth arrest through activation of the Janus kinase (Jak) /signal transducers and activators of transcription (Stat) signal path way in murine MI myeloid leukaemia cells, Treatment of various other m yeloid leukaemia lines with LIF or IL-6 did not lead to induction of d ifferentiation, Several defects in the cytokine triggered Jak/Stat sig nal pathway were striking in these lines, They expressed a decreased o r undetectable amount of at least one of the components of the specifi c 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 ve ry low density of IL-6-receptors. Apart from the cytokine receptors, a dditional components of the Jak/Stat signal cascade were altered in th ese lines, Expression and activation of the transcription factor Stat5 a and the tyrosine kinase Jak2 were markedly decreased compared to M1 cells, suggesting a role of activated Stat5a in the induction of diffe rentiation, These results demonstrate a direct correlation between alt erations in the Jak/Stat signal pathway and the inability-to different iate after cytokine treatment of myeloid leukaemia cells. (C) 1997 Aca demic Press Limited.