Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells viatranscriptional repression of STAT 5 and Mcl-1

Expression of the transcription repressor Gfi-1 is required for the maintenance of murinehematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNAinterference-mediated Gfi-1 downregulation enhances proliferation and colony formationof p210BCR/ABL-expressing cells.To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1expression in human cells, Gfi-1-regulated genes were identified by microarray analysisin K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein. STAT 5B and Mcl-1,two genes important for the proliferation and survival of hematopoietic stem cells, wereidentified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformedcells because: i) their expression and promoter activity was repressed by Gfi-1; and ii)when constitutively expressed blocked the proliferation and colony formation inhibitoryeffects of Gfi-1.Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/orMcl-1 markedly suppressed proliferation and colony formation of K562 and CD34+CML cells.Together, these studies suggest that the Gfi-1→ STAT 5B/Mcl-1 regulatory pathwayidentified here can be modulated to suppress the proliferation and survival ofp210BCR/ABL-transformed cells including CD34+ CML cells.