Critical prosurvival roles for C/EBPβ and insulin-like growth factor I in macrophage tumor cells

One of the hallmarks of leukemic cells is their ability to proliferate and survive in the absence of exogenous growth factors (GFs). However, the molecular mechanisms used by myeloid tumor cells to escape apoptosis are not fully understood. Here we report that Myc/Raf- transformed macrophages require the transcription factor C/EBPbeta to prevent cell death. In contrast to wild-type cells, C/EBPbeta(-/-) macrophages were completely dependent on macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for survival and displayed impaired tumorigenicity in vivo. Microarray analysis revealed that C/EBPbeta-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBPbeta stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBPP. Serological neutralization of IGF-I in C/EBPbeta(+/+) tumor cell cultures induced apoptosis, showing that IGF-I functions as an autocrine survival factor in these cells. Macrophage tumor cells derived from IGF-I-/- mice were GF dependent, similar to C/EBPO-deficient cells. Forced expression of either C/EBPP or IGF-I in C/EBPbeta(-/-) bone marrow cells restored Myc/Raf-induced transformation and permitted neoplastic growth without exogenous GFs. Thus, our findings demonstrate that C/EBPD is essential for oncogenic transformation of macrophages and functions at least in part by regulating expression of the survival factor IGF-I.