Gadd45a Behaves as a Tumor Suppressor and Gadd45b Behaves as an Oncogene in myc-Mediated Block in Myeloid Differentiation.

Abstract

We have observed that deregulated c-Myc expression in M1 myeloid leukemic cells blocks IL-6-induced differentiation at an intermediate stage, the cells fail to exit the cell cycle, proliferating indefinitely, with a portion of the cells always undergoing apoptotic cell death by prematurely recruiting the CD95/Fas apoptotic pathway. Similar results were also observed in normal myeloid cells from bone marrow (Amanullah et al. Oncogene 19:2967–77, 2000; Amanullah et al. Oncogene 21:1600–1610, 2002). Although there is evidence that c-myc represses the gadd45a promoter, this laboratory has observed elevated gadd45a expression in M1myc cells that are blocked during differentiation. In addition, microarray analysis indicated that gadd45b is a c-myc target gene. Because of these observations and the availability of gadd45a null and gadd45b null mice, the effect of deregulated myc expression in Hoxb8 immortalized macrophage progenitors was ascertained. It was observed that deregulated c-myc expression in gadd45a null cells blocked differentiation at the blast stage, compared to a block at the intermediate stage for wild type progenitors. In contrast, deregulated c-myc expression in gadd45b null progenitors resulted in rapid cell death. These observations suggest that in the context of myc mediated myeloid leukemias Gadd45a behaves as a tumor suppressor and Gadd45b behaves as an oncogene.