The proto-oncogene c-myc in hematopoietic development and leukemogenesis

The proto-oncogene c-myc has been shown to play a pivotal role in cell cycle regulation, metabolism, apoptosis, differentiation, cell adhesion, and tumorigenesis, and participates in regulating hematopoietic homeostasis. It is a transcription regulator that is part of an extensive network of interacting factors. Most probably, different biological responses are elicited by different overlapping subsets of c-Myc target genes, both induced and suppressed. Results obtained from studies employing mouse models are consistent with the need for at least one, and possibly two, mutations in addition to deregulated c-myc for malignant tumor formation. Repression of c-myc is required for terminal differentiation of many cell types, including hematopoietic cells. It has been shown that deregulated expression of c-myc in both M1 myeloid leukemic cells and normal myeloid cells derived from murine bone marrow, not only blocked terminal differentiation and its associated growth arrest, but also induced apoptosis, which is dependent on the Fas/CD95 pathway. There is evidence to suggest that the CD95/Fas death receptor pathway is an integral part of the apoptotic response associated with the end of the normal terminal myeloid differentiation program, and that deregulated c-myc expression can activate this signaling pathway prematurely. The ability of egr-1 to promote terminal myeloid differentiation when co-expressed with c-myc, and of c-fos to partially abrogate the block imparted by deregulated c-myc on myeloid differentiation, make these two genes candidate tumor suppressors. Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1. Alterations in the expression and/or function of these transcription factors, or of the c-Myc and Max interacting proteins, such as MM-1 and Mxi1, can influence the neoplastic process. Understanding how c-Myc controls cellular phenotypes, including the leukemic phenotype, should provide novel tools for designing drugs to promote differentiation and/or apoptosis of leukemic cells.