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

Abstract

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.

Antiangiogenic Effects and Therapeutic Targets ofAzadirachta indicaLeaf Extract in Endothelial Cells

“…However, although several studies have shown EGR-1 promotes cancer progression, there is increasing evidence that EGR-1 may also exerts tumor suppression [42, 43]. In leukemia, EGR-1 has been implicated in the apoptosis of myeloma cells via interaction with c-JUN while it behaves as a tumor suppressor against the oncogenes E2F-1 and c-MYC [44]. EGR-1 activation by EGF inhibited MMP9 expression and lymphoma growth [45].…”

The progress of early growth response factor 1 and leukemia

“…EGR1 is also important for development of the macrophage lineage (96). It is interesting to note that 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 (97). A novel mechanism of thalidomide in the treatment of leukemia is that thalidomide could suppress leukemia cell invasion and migration by upregulation of EGR-1 (98).…”

Identification of uniquely expressed transcription factors in highly purified B‐cell lymphoma samples

“…2, Table III and Table SI), tumor suppressor genes or TFs regulating tumor suppressors were identified for all of the entities including expression of FOXO1 [22] in FL cells, PA2G4 [23] in DLBCL cells, SOX11 [24] in MCL cells, and PRDM2 [25] in CLL. Furthermore, SOX4 and EGR1, known depending on tumor type, to act both as tumor suppressors [26][27][28][29] and oncogenes [30,31] showed lower expression in CLL cells. Finally, HCL cells had a high expression of SOX4, and also a low expression of FOXP1 [32].…”