title: Egr-1 abrogates the E2F-1 block in terminal myeloid differentiation and suppresses leukemia.
abstract: Deregulated growth and blocks in differentiation collaborate in the multistage process of leukemogenesis. Previously, we have shown that ectopic expression of the zinc finger transcription factor Egr-1 in M1 myeloblastic leukemia cells promotes terminal differentiation with interleukin-6 (IL-6). In addition, we have shown that deregulated expression of the oncogene E2F-1 blocks the myeloid terminal differentiation program, resulting in proliferation of immature cells in the presence of IL-6. Here it is shown that the positive regulator of differentiation Egr-1 abrogates the E2F-1-driven block in myeloid terminal differentiation. The M1E2F-1/Egr-1 cells underwent G(0)/G(1) arrest and functional macrophage maturation following treatment with IL-6. Furthermore, Egr-1 diminished the aggressiveness of M1E2F-1 leukemias and abrogated the leukemic potential of IL-6-treated M1E2F-1 cells. Previously, we reported that Egr-1 abrogated the block in terminal myeloid differentiation imparted by deregulated c-myc, which blocks differentiation at a later stage than E2F-1, resulting in cells that have the characteristics of functionally mature macrophages that did not undergo G(0)/G(1) arrest. Taken together, this work extends and highlights the tumor suppressor role of Egr-1, with Egr-1 behaving as a tumor suppressor against two oncogenes, each blocking myeloid differentiation by a different mechanism. These findings suggest that Egr-1 and/or Egr-1 target genes may be useful tools to treat or suppress oncogene-driven hematological malignancies.
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Gibbs
authors.forename: D A
authors.initials: DA
authors.lastname: Liebermann
authors.forename: B
authors.initials: B
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000502:physiology*; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006131:Growth Inhibitors; D015850:Interleukin-6; D025521:Tumor Suppressor Proteins