To define molecular signatures of c-myc-induced B-cell neoplasias we have explored, using DNA microarrays, gene expression profiles at various stages of tumorigenesis utilizing the transgenic Em-myc model1. In this system c-myc is expressed, under the control of the immunoglobulin heavy-chain enhancer, selectively in B-cell precursors, and it causes the rapid appearance of B-cell lymphomas. Overt tumors are preceded by a marked polyclonal expansion of pre-B cells both in the bone marrow and in the spleen. However, these cells are not yet tumorigenic. Within a few months the Em-myc mice develop a monoclonal or oligoclonal lymphoma. We monitored gene expression changes using an 11,000-gene chip (Affymetrix) of pre-B cells derived from the bone marrow of Em-myc mice before tumor development and cells from lymphomas, consisting primarily of pre-B cells. Both samples were then compared with normal pre-B lymphocytes obtained from bone marrow of wild-type mice. The data analysis allowed a display of gene expression changes that accompany these various stages of tumor development. Preliminary results indicate that specific signaling pathways are selectively altered in the tumor samples or in the hyperplastic pre-B cells. In addition, comparison of the pre-B cells expressing Em-myc with wild-type pre-B cells highlighted gene expression changes that might be direct consequences of deregulated c-myc expression and therefore provided new candidate Myc target genes. We will present a discussion of the relevance of our study for the understanding of c-myc-induced tumorigenesis.