Egr-1 Functions as a Tumor Suppressor for Leukemias Caused by Different Oncogenes.

Abstract

Deregulated expression of the proto-oncogenes c-myc, E2F-1 and c-myb in M1 myeloid leukemic cells rendered these cells incapable of undergoing myeloid terminal differentiation and its associated growth arrest, and prevented the loss in leukemogenicity normally observed when M1 cells are induced to differentiate. We recently showed that expressing Egr-1 in M1myc cells abrogated the c-myc-mediated block in terminal myeloid differentiation, with the cells undergoing macrophage maturation in the absence of growth arrest. Importantly, Egr-1 also abrogated c-myc-driven leukemogenicity. In this study, we asked if Egr-1 functions as a tumor suppressor by abrogating the block in differentiation caused by other oncogenes. It was shown that expressing Egr-1 in M1E2F-1 cells completely overrode the block in terminal myeloid cell differentiation, with the cells undergoing macrophage maturation, and unlike in myc/Egr-1 expressing cells, also becoming growth arrested. In contrast, expression of Egr-1 in M1myb cells promoted progression of the differentiation program to an intermediate stage of differentiation, but the cells became neither fully matured nor growth arrested, continuing to proliferate indefinitely. As seen for expression of Egr-1 in M1myc cells, Egr-1 expression in M1E2F-1 cells also abrogated E2F-1 driven leukemogenicity. In contrast, Egr-1 co-expression with c-myb in M1myb cells did not abrogate myb driven leukemia. Taken together, it can be concluded that Egr-1 is dominant to both E2F-1 and c-myc with regard to terminal morphological differentiation and the ability to suppress leukemias, whereas the proto-oncogene c-myb is dominant to Egr-1. These findings indicate that the tumor suppressor Egr-1 provides important tools for differentiation therapy of multiple leukemic phenotypes, dependent on the molecular nature of the activated oncogene.