POSITIVE SELECTION OF APOPTOSIS-RESISTANT CELLS CORRELATES WITH ACTIVATION OF DOMINANT-NEGATIVE STAT5

The STATE activation has important roles in cell differentiation, cell cycle control, and development. However, the potential implications o f STATE in the control of apoptosis remain unexplored. To evaluate any possible link between the erythropoietin receptor (EpoR) JAK2/STAT5 t ransduction pathway and apoptosis, we have investigated apoptosis-resi stant cells (ApoR) that arose from positive selection of the erythroid -committed Ba/F3EpoR cells triggered to apoptosis by ectopic expressio n of the HOX-B8 homeotic gene, We show that JAK2 is normally activated by Epo in both Ba/F3EpoR and ApoR cells, In contrast, both STAT5a and STAT5b isoforms are uniquely activated in a C-truncated form (86 kDa) only in ApoR cells. Analysis of ApoR and Ba/F3EpoR subclones confirme d that the switch to the truncated STATE isoform coincides with apopto sis survival and that ApoR do not derive from preexisting cells with a shortened STATE. In addition, ApoR cells die in the absence of Epo, T his indicates that resistance to apoptosis is not because of a general defect in the apoptotic pathway of ApoR cells. Furthermore, we show t hat the 86-kDa STATE protein presents a dominant-negative (DN) charact er. We hypothesize that the switch to a DN STATE may be part of a mech anism that allows ApoR cells to be selectively advantaged during apopt osis. In conclusion, we provide evidence for a functional correlation between a naturally occurring DN STATE and a biological response.