The cellular proto-oncogene c-myc is an important transcription factor that plays a role in several cellular activities such as proliferation, differentiation, and apoptosis. It follows that regulation of c-myc expression is crucial for maintaining cell integrity. Amplification or translocation can convert this proto-oncogene into an activated oncogene, thereby deregulating c-myc expression. Changes in the expression of c-myc leading to malignant cell growth and tumor progression can also be triggered by extrinsic factors. It has been reported that iron can increase cell proliferation, mainly by stimulating DNA synthesis as well as by enhancing c-myc expression. Here, we studied the effect of iron on cells in which c-myc expression is deregulated by either chromosomal translocation or gene amplification. When added to Burkitt's lymphoma cell lines, iron markedly inhibits cell proliferation. This effect is mediated by a cell cycle arrest in G2/M, followed by an important decrease in c-myc expression, whereas no effect could be observed in a cell line harboring amplified c-myc. Moreover, the down-regulation of c-myc expression, which is independent from cell cycle blockade, leads to cell death by apoptosis. Collectively, our results suggest the existence of a novel iron-dependent cell cycle regulatory mechanism involving modulation of translocated c-myc gene expression. © 2004 Wiley-Liss, Inc.