Bcr/Abl activates transcription of the Bcl-X gene through STAT5

Several tyrosine kinase oncogenes have been associated with myeloproliferat ive diseases, including Bcr/Abl, Tel/Abl, Tel/Jak2, and Tel/PDGFR. One targ et molecule shared by these oncogenes is known to be STAT5. We generated su blines of Ba/F3 cells in which either wild-type STAT5 or a constitutively a ctive mutant of STAT5 (STAT5-1*6) were expressed under the control of a tet racycline-inducible promoter. These cell lines were compared with a Ba/F3 c ell line in which the expression of p210(Bcr/Abl) was made inducible by a s imilar promoter. Before induction, all cells were dependent on interleukin 3 (IL-3) for growth and survival. Both STAT5-1*6 and Bcr/Abl enhanced viabi lity and induced proliferation in the absence of IL-3. We found that the pr oviability protein Bcl-X-L, but not Bcl-2, was induced by both p210(Bcr/Abl ) and STAT5-1*6. Using a Bcl-X gene promoter construct fused to a luciferas e complementary DNA (cDNA), both p210(Bcr/Abl) and STAT5-1*6 were shown to induce transcription of Bcl-X. The increase in transcription of the Bcl-X p romoter and the increase in Bcl-X protein, due to p210(Bcl/Abl), were block ed by expression of a dominant negative STAT5 mutant, Interestingly, howeve r, STAT5-1*6 required the continued presence of IL-3 to cause a significant increase in Bcl-X-L protein, whereas p210(Bcr/Abl) did not need IL-3. Stud ies with enzyme inhibitors suggest that the extra signal supplied by IL-3 m ay be supplied by the PI3K pathway. Overall, these data suggest that consti tutively activated STAT5 can increase viability and proliferation of Ba/F3 cells. This may contribute to, but is not likely sufficient for, the enhanc ed viability associated with Bcr/Abl transformation. (Blood, 2000;96:2269-2 276) (C) 2000 by The American Society of Hematology.