Leukemia suppressor function of Egr-1 is dependent on transforming oncogene.

We have shown that deregulated expression of either c-Myb or E2F-1 blocks terminal differentiation of M1 myeloid leukemia cells at the blast stage, whereas deregulated c-Myc blocks differentiation at the intermediate stage. Each of these oncogenes potentiates M1 leukemia in vivo. The zinc-finger transcription factor Egr-1 abrogates the block in M1 terminal differentiation imparted by oncogenic c-Myc or E2F-1, suppressing their leukemia-promoting function in nude mice. In this study, we asked whether Egr-1 also abrogates the block in terminal differentiation and suppresses leukemia imparted by deregulated c-Myb. Interestingly, the ectopic expression of Egr-1 in M1 cells expressing deregulated c-Myb only partially abrogated the block in terminal differentiation and did not suppress the leukemic phenotype. Two important implications from these data are that the leukemia suppressor function of Egr-1 is not directly related to how early the transforming oncogene blocks the differentiation program and that the tumor suppressor function of Egr-1 is dependent on the specific oncogene. Egr-1 is dominant to c-Myc- and E2F-1-, but not to c-Myb-, driven leukemia. These findings extend the notion that the molecular nature of genetic lesions responsible for leukemia determines the effectiveness of any given tumor suppressor.

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.