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

A. R. Soliera, S. A. Mariani, A. Audia, M. R. Lidonnici, S. Addya, G. Ferrari-Amorotti, S. Cattelani, G. Manzotti, V. Fragliasso, L. Peterson, G. Perini, T. L. Holyoake, B. Calabretta

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1555-1563
Number of pages9
JournalLeukemia
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 2012

Keywords

  • cell survival
  • oncogene
  • therapy
  • tumor suppressor gene

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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    Soliera, A. R., Mariani, S. A., Audia, A., Lidonnici, M. R., Addya, S., Ferrari-Amorotti, G., Cattelani, S., Manzotti, G., Fragliasso, V., Peterson, L., Perini, G., Holyoake, T. L., & Calabretta, B. (2012). Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1. Leukemia, 26(7), 1555-1563. https://doi.org/10.1038/leu.2012.19