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 of STATE in the control of apoptosis remain unexplored. To evaluate any possible link between the erythropoietin receptor (EpoR) JAK2/STAT5 transduction pathway and apoptosis, we have investigated apoptosis-resistant cells (ApoR) that arose from positive selection of the erythroid-committed Ba/F3EpoR cells triggered to apoptosis by ectopic expression 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 confirmed that the switch to the truncated STATE isoform coincides with apoptosis survival and that ApoR do not derive from preexisting cells with a shortened STATE. In addition, ApoR cells die in the absence of Epo, This indicates that resistance to apoptosis is not because of a general defect in the apoptotic pathway of ApoR cells. Furthermore, we show that the 86-kDa STATE protein presents a dominant-negative (DN) character. We hypothesize that the switch to a DN STATE may be part of a mechanism that allows ApoR cells to be selectively advantaged during apoptosis. In conclusion, we provide evidence for a functional correlation between a naturally occurring DN STATE and a biological response.