期刊
LEUKEMIA
卷 26, 期 7, 页码 1555-1563出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.19
关键词
cell survival; oncogene; tumor suppressor gene; therapy
资金
- National Cancer Institute [CA 95111, P01 78890]
- Cancer Research UK Program [C11074/A11008]
- Glasgow Experimental Cancer Medicine Centre (ECMC)
- American-Italian Cancer Foundation (AICF)
- Associazione Italiana Ricerca sul Cancro (AIRC)
- Fondazione Cassa di Risparmio di Vignola
- AIRC/Marie Curie Foundation
- Cancer Research UK [11008] Funding Source: researchfish
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.
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