C-MYC REARRANGEMENTS IN HEMATOPOIETIC NEOPLASIAS

The general objective of this research project is to elucidate the mechanism by which deregulated expression of the c-Myc gene induce B-cell neoplasia. The c-Myc gene encodes a transcription factor which binds DNA specifically as an heterodimer with its partner protein Max and regulates cell proliferation, differentiation and apoptosis by regulating the expression of specific target genes. Despite the substantial progress in elucidating the function of c- Myc, the identity of c-Myc target genes, and therefore the mechanism by which c-Myc contributes to tumorigenesis, remains unknown. We have recently developed novel experimental strategies for the identification of c-Myc target genes based on the use of non-transformed. EBV-immortalized human B cells as substrates for the identification of c-Myc regulated genes. Using this approach, we have identified two novel c-Myc target genes: I) Mxi which codes for a transcription factor which antagonizes the function of c-Myc by heterodimerizing with Max. Mxi expression is induced by c-Myc suggesting that Myc-mediated inducted of Mxi may be part of an autoregulatory circuit that modulates c-Myc function; ii) H-ferritin, whose expression is suppressed by c-Myc, and whose enforced expression can revert part of Myc-dependent transformation phenotype, suggesting that H-ferritin downregulation may represent a critical component of the Myc-dependent biological program. Finally, we have established a novel system allowing for the first time the identification of genes that are regulated upon c- Myc induction in normal quiescent cells (B cells), the physiologic context of c-Myc induction. Based on these approaches, the long term goal of this project is to identify the full spectrum of c-Myc target genes and test their ability, individually or in combination, to reproduce part of the c-Myc-dependent phenotype. The identification of these genes should be instrumental in understanding the mechanism by which c-Myc regulates growth, differentiation and apoptosis, as well as its precise contribution to tumorigenesis.