Challenging E2F-1 and c-Myb Block of Myeloid Terminal Differentiation with the Tumor Suppressor-Egr1.

The proliferation and differentiation of hematopoietic cells are tightly regulated to maintain cellular homeostasis. Understanding the mechanism of this regulation may identify potential therapeutic targets against leukemia. Previous works have shown that several negative regulators of differentiation, namely oncogenes c-Myb, E2F-1 and c-Myc were capable of blocking the IL6-mediated myeloid terminal differentiation program of M1 myeloblastic leukemia cells. On the other hand, a positive regulator of differentiation, Egr-1 has been shown to activate the macrophage differentiation program of M1 cells in the absence of IL-6. Interestingly, recent work showed that Egr-1 could override the block of differentiation imparted by deregulated c-Myc in the presence of IL-6, and could reverse the leukemic phenotype associated with deregulated c-Myc. From such observations, we asked whether exogenous expression of Egr-1 in M1 cells could override the earlier block of differentiation imparted by the oncogenes c-Myb or E2F-1. The established M1Myb-Egr cells and M1E2F-Egr cells were analyzed. The M1E2F-Egr cells underwent growth arrest followed by macrophage differentiation and subsequently apoptosis. In addition, exogenous Egr-1 only partially abrogated c-Myb block of differentiation. The M1Myb-Egr cells failed to undergo growth arrest, however, were able to enter intermediate-late stage macrophage differentiation with concomitant phagocytic functionality. These data demonstrate that E2F and c-Myb each block myeloid differentiation via different mechanisms. Egr-1 can completely override the E2F block but cannot abrogate the c-Myb block to allow M1 cells to terminally differentiate or growth arrest. Furthermore, Egr-1 appears to behave as a tumor suppressor, and therefore may serve as a possible target against various forms of leukemia.