Egr-1 abrogates the block imparted by c-Myc on terminal M1 myeloid differentiation.
Both deregulated growth and blocks in differentiation cooperate in the multistage process of leukemogenesis. Thus, understanding functional interactions between genes that regulate normal blood cell development, including cell growth and differentiation, and how their altered expression contributes to leukemia, is important for rational drug design. Previously, we have shown that the zinc finger transcription factor Egr-1 plays a role in monocytic differentiation. Ectopic expression of Egr-1 in M1 myeloblastic leukemia cells was observed to activate the macrophage differentiation program in the absence of the differentiation inducer interleukin 6 (IL-6) and to promote terminal differentiation in its presence. In addition, we have shown that deregulated expression of the proto-oncogene c-myc blocks the myeloid terminal differentiation program. Here we show that restoring expression of Egr-1 in M1 cells that express deregulated c-Myc abrogates the c-Myc block in terminal differentiation, resulting in cells that undergo functional macrophage maturation. However, there is an absence of both growth arrest and cell adhesion. In addition, Egr-1 expression diminished M1myc leukemogenicity in vivo. These findings indicate that Egr-1 can act as a tumor suppressor gene and suggest that Egr-1 or Egr-1 targets may provide important tools for differentiation therapy in certain leukemic phenotypes.
Shafarenko
Marianna
M
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N Broad St, Philadelphia, PA 19140, USA.
Liebermann
Dan A
DA
Hoffman
Barbara
B
D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology*; D051766:Early Growth Response Protein 1; D016147:Genes, Tumor Suppressor; D017874:Immediate-Early Proteins / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000473:pathology*; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors