To search for genes that can collaborate with myc in lymphomagenesis, we exploited retroviral insertional mutagenesis in Ep-myc transgenic mice. Moloney murine leukemia virus accelerated development of B lymphoid tumors. Three quarters conta’ined a provirus within the known pim-1 or pim-2 loci, new loci bmC1 and emi-l, or combinations of these. bmi-1 insertions predominated, occurring in half the tumors, and resulted in elevated bmi-1 mRNA levels. Significantly, the bmi-1 gene, which is expressed in diverse normal cells, encodes a Cys/His metal-binding motif (CsHC,) that resembles those in several DNA-binding proteins and defines a new category of zinc finger gene. Thus, myc-induced lymphomagenesis can entail the concerted action of several genes, including the presumptive nuclear regulator bmi-1. introduction

New approaches to tumorigenesis are provided by transgenie mice bearing oncogenes expressed in specific tissues (reviewed by Cory and Adams, 1988; Jaenisch, 1988; Hanahan, 1989). Among transgenic models of hematopoietic malignancies (reviewed by Adams and Cory, 1991), the best studied are mice bearing the myc oncogene coupled to an immunoglobulin heavy chain enhancer (Ep)(Adams et al., 1985; Harris et al., 1988; Schmidt et al., 1988). The constitutive expression of the myc gene within the B lymphocyte cbmpartment of Ew-myc mice promotes a benign polyclonal overproduction of cycling pre-B cells (Langdon et al., 1986), and all the mice eventually succumb to a clonal pre-B or B cell lymphoma (Harris et al., 1988; Schmidt et al., 1988). Since neither the structure nor expression of the transgene is detectably altered in the tumors (Alexander et al., 1987; Webb et al., 1989), the malignant clones most likely arise by spontaneous alterations of one or more independent genes that act in concert with the myc gene. In keeping with that notion, 2 of 14 Ep-myc lymphomas proved to bear a mutated ras gene (Alexander et al., 1989b), and lymphomagenesis could be accelerated by introducing a ras or raf oncogene into the preleukemic cells (Alexander et al., 1989a, 1989b; Lang-