MO-MLV infection of Ep-myc transgenic mice results in a dramatic acceleration of pre-B ceil iymphomagenesis. We have used provirus tagging to identify genes that cooperate with the EP-myc transgene in B ceil transformation. Here we report on the identification of four loci,@ ml, bmi-1, pal-l, and b/al, which are occupied by proviruses in 35%, 35%, 28%, and 14% of the tumors, respectively. bmi-1, pa/-l, and b/al represent novel common provirai insertion sites. The bmi-1 gene encodes a 324 amino acid protein with a predominantly nuclear localization. bmi-1 is highly conserved in evolution and contains several motifs frequently found in transcriptional regulators, including a new putative zinc finger motif. No genes have yet been assigned to pal-l and b/al. The distribution of proviruses over the four common insertion sites suggests that provirus tagging can be used not only to identify the cooperating oncogenes but also to assign these genes to distinct compiementation groups in tumorigenesis. introduction

Deregulation of c-myc gene expression has been impiicated in many neoplasias, especially in tumors of the hematopoietic system. Mechanisms of activation include chromosomai translocations, amplification, and insertionai activation by retroviruses. Although the exact function of the c-myc gene is still elusive, its expression is associated with cell cycling (reviewed in Cole, 1988; Cory and Adams, 1988). For example, mouse erythroid leukemia cells that constitutiveiy express c-myc continue to proliferate and cannot be induced to differentiate to more mature nonproliferating hemoglobin-producing ceils (Coppoia and Cole, 1988; Prochownik and Kukowska, 1988). Since the c-myc gene encodes two nuclear phosphoproteins that contain several structural motifs known to be involved in DNA-binding and protein-protein interactions,