CHARACTERIZATION OF FACTOR-INDEPENDENT VARIANTS DERIVED FROM TF-1 HEMATOPOIETIC PROGENITOR CELLS - THE ROLE OF THE RAF MAP KINASE PATHWAY IN THE ANTI-APOPTOTIC EFFECT OF GM-CSF/

Human hematopoietic progenitor cells (TF-I) undergo apoptosis upon dep rivation of their dependent cytokine, In this report, we have isolated and characterized some spontaneously derived cytokine-independent var iants from TF-1 cells, Analysis of several signaling molecules known t o be activated by the GM-CSF pathway revealed that two non-autocrine v ariants were still responsive to GM-CSF stimulation, However, both var iants, without ligand stimulation, already had some activated forms of Raf and MAP kinases, Given current knowledge, the activated Raf/MAP k inase pathway was likely to be responsible for the survival of both va riants in the cytokine-free medium, However, the growth of hybrids bet ween wild type and either variant was unexpectedly dependent on GM-CSF , Both variants like the wild type cells were still susceptible to apo ptosis induced by other stimuli, These results suggest that either the activated Raf/MAP kinase pathway in both variants fs not sufficient t o repress the 'two-fold' death signals generated from the hybrids or t hat there is another mechanism that is responsible for the factor-inde pendent growth of both variants.