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. Interestingly, it was shown that the ability of Egr-1 to override the c-Myc block in terminal differentiation occurred in the absence of growth arrest and cell adhesion, resulting in cells with the characteristics of functionally mature macrophages. As with normal macrophages, the cells also underwent programmed cell death. It was also observed that Egr-1 diminished the aggressiveness of M1myc leukemias, and abrogated the leukemic potential of M1myc cells treated with IL-6. Taken together, these observations demonstrate that Egr-1 behaves like a tumor suppressor, suggesting that, on the one hand, genetic lesions which alter Egr-1 expression can cooperate with deregulated c-Myc in exacerbating the leukemic phenotype and, on the other hand, that enhancement of Egr-1 expression, or its downstream targets, can overcome blocks in differentiation due to deregulated c-Myc, as well as its associated leukemias These findings suggest that Egr-1 and/or Egr-1 targets may provide important tools for differentiation therapy in certain leukemic phenotypes