title: Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1.
abstract: Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in 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, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34+ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34+ CML cells.
authors.affiliation: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
authors.forename: A R
authors.initials: AR
authors.lastname: Soliera
authors.forename: S A
authors.initials: SA
authors.lastname: Mariani
authors.forename: A
authors.initials: A
authors.lastname: Audia
authors.forename: M R
authors.initials: MR
authors.lastname: Lidonnici
authors.forename: S
authors.initials: S
authors.lastname: Addya
authors.forename: G
authors.initials: G
authors.lastname: Ferrari-Amorotti
authors.forename: S
authors.initials: S
authors.lastname: Cattelani
authors.forename: G
authors.initials: G
authors.lastname: Manzotti
authors.forename: V
authors.initials: V
authors.lastname: Fragliasso
authors.forename: L
authors.initials: L
authors.lastname: Peterson
authors.forename: G
authors.initials: G
authors.lastname: Perini
authors.forename: T L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: B
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008156:Luciferases / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D020411:Oligonucleotide Array Sequence Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D008156:Luciferases; C520962:obatoclax