The proto-oncogene c-myc has been shown to play a pivotal role in cell cycle regulation, metabolism, apoptosis, dierentiation, 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, dierent biological responses are elicited by dierent 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 dierentiation 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 dierentiation 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 dierentiation program, and that deregulated c-myc expression can activate this signaling pathway prematurely. The ability of egr-1 to promote terminal myeloid dierentiation when coexpressed with c-myc, and of c-fos to partially abrogate the block imparted by deregulated c-myc on myeloid dierentiation, make these two genes candidate tumor suppressors. Several dierent transcription factors have been implicated in the down-regulation of c-myc expression during dierentiation, including C/EBPa, 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 in¯uence the neoplastic process. Understanding how c-Myc controls cellular phenotypes, including the leukemic phenotype, should provide novel tools for designing drugs to promote dierentiation and/ or apoptosis of leukemic cells.

No abstract

GlaxoSmithKline Biologicals SA.

Previously we have shown that deregulated expression of c-myc in M1 myeloid leukemic cells blocked IL-6-induced dierentiation and its associated growth arrest; however, the cells proliferated at a signi®cantly reduced rate compared to untreated cells. The basis for the increased doubling time of IL-6-treated M1myc cells was found to be due to the induction of a p53-independent apoptotic pathway. The apoptotic response was not completely penetrant; in the same population of cells both proliferation and apoptosis were continuously ongoing. Down-regulation of Bcl-2 was insucient to account for the apoptotic response, since deregulated expression of Bcl-2 delayed, but did not block, the onset of apoptosis. Furthermore, our results indicated that the IL-6-induced partial hypophosphorylation of the retinoblastoma gene product (Rb), observed in M1myc cells, was not responsible for the apoptotic response. Finally, the ®ndings in M1 cells were extended to myeloid cells derived from the bone marrow of wild type and p53-de®cient mice, where the deregulated expression of c-myc was also shown to block terminal dierentiation and induce apoptosis independent of p53. These ®ndings provide new insights into how myc participates in the neoplastic process, and how additional mutations can promote more aggressive tumors.