Transgenic models of lymphoid neoplasia and development of a pan-hematopoietic vector JM Adams* ,1 , AW Harris 1 , A Strasser 1 , S Ogilvy 1 and S Cory 1 1 The Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia The pathways to lymphoid neoplasia have been explored in a number of transgenic models. Because B lymphoid malignancies often involve translocation of an oncogene (e.g. myc, bcl-2, cyclin D1) to an immunoglobulin locus, resulting in its deregulated expression, the consequences of oncogene overexpression in lymphocytes can be evaluated with transgenes driven by an immunoglobulin regulatory element, such as an enhancer from the IgH locus. Mice bearing such transgenes have provided insight into the preneoplastic state, including alterations in the control of cellular proliferation, dierentiation or apoptosis. They have also allowed studies on oncogene cooperation in vivo and the modulating eect of genetic background. Brie¯y reviewed here are the models studied in the authors' laboratories. Mice bearing myc and bcl-2 transgenes have received most attention but others studied include abl, ras, cyclin D1 and bmi-1 oncogenes. Also discussed is a new transgenic vector that should facilitate transgenic approaches to non-lymphoid leuke- mias. The vector bears elements from the promoter region of the vav gene, which is expressed almost exclusively in hematopoietic cells. It has proven capable of driving transgene expression throughout the hemato- poietic compartment, including progenitor cells and their precursors. This novel vector should aid studies on many aspects of hematopoiesis, including the modeling of leukemogenesis. Keywords: lymphoma; leukemia; oncogene; transgenic vectors; hematopoiesis As reviewed previously (Cory and Adams, 1988; Adams and Cory, 1991a,b; Adams et al., 1991), transgenic models have provided an invaluable resource for molecular oncology by revealing the consequences of putative tumorigenic mutations in the most relevant context, namely the living animal. With an appropriate choice of regulatory elements, the impact of an oncogene can be studied in the most pertinent normal cell type rather than in cell lines that have unknown and variable mutational histories. As well as tumorigenic potential, one can evaluate how the introduced oncogene aects cell cycling, dierentiation and apoptosis. These models provide new avenues to study the pre-neoplastic state, including long-term pathological eects. Moreover, the enhanced suscept- ibility of the relevant cell population in these animals to chemical and biological agents makes them an important resource for uncovering the various path- ways to full ¯edged malignancy. In particular, cross breeding of two cancer-prone strains can test cooperativity between dierent known oncogenic mutations. Moreover, insertional mutagenesis with retroviruses can be used to identify oncogenic partners, including previously unknown genes. Final- ly, the availability of numerous inbred strains of mice, which can vary markedly in susceptibility to dierent types of malignancies, raises the prospect of uncovering modi®er loci that in¯uence the impact of particular oncogenes or tumor suppressor genes. The strengths of this experimental approach ensure that mice engineered to express particular oncogenes or to lack speci®c tumor suppressors will continue to illuminate the complex genetic scenario that underlies malignancy. The ®rst aim of this review will be to sketch some of the ®ndings from transgenic models for lymphomagen- esis, with illustrations drawn mainly from studies in our own laboratories. Our studies were triggered by an interest in the translocations found in B-lymphoid tumors, which almost invariably couple a putative oncogene to an immunoglobulin locus, thereby subjecting the translocated gene to regulatory elements of that locus, such as the enhancer (Em) near the Cm gene (Cory, 1986). Consequently, our ®rst transgenic study mimicked the prototypic myc-Igh translocation by linking Em to the c-myc gene (Adams et al., 1985), and that regulatory element has also featured in much of our subsequent work. The models we have studied are summarized in Table 1. More extensive discussion of these and other models of lymphomagenesis, including related work by other laboratories, can be found in earlier reviews (Cory and Adams, 1988; Adams and Cory, 1991a,b; Adams et al., 1991; Berns et al., 1994; Jonkers and Berns, 1996; Chao and Korsmeyer, 1998). Because the role played in tumor- igenesis by altered apoptosis has increasingly occupied our attention, several of our other reviews concentrate on how its prototypic regulator Bcl-2 (Vaux et al., 1988) aects normal lymphoid homeostasis and contributes to lymphomagenesis (Cory et al., 1994a,b; Cory, 1995; Strasser, 1995b, 1999; Strasser et al., 1996b, 1997a,b; Cory et al., 1999). Eective transgenic vectors for the lymphoid compartment have been essential for the development of lymphomagenic models. The transgenic analysis of non-lymphoid leukemias has been more problematic (Westervelt and Ley, 1999), in part because the available vectors for myeloid cells are active in only a single lineage or at a speci®c stage of dierentiation (e.g. Lagasse and Weissman, 1994). On the other hand, a vector expressed widely in the hematopoietic system but also in other tissues, such as the class I MHC promoter (Domen et al., 1998), might lead to confusing *Correspondence: JM Adams Oncogene (1999) 18, 5268 ± 5277 ã 1999 Stockton Press All rights reserved 0950 ± 9232/99 $15.00 http://www.stockton-press.co.uk/onc