Egr-1 abrogates the E2F-1 block in terminal myeloid differentiation and suppresses leukemia.
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.
Gibbs
J D
JD
Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA.
Liebermann
D A
DA
Hoffman
B
B
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*
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