We have continued our studies on chromosomal translocations that result in the deregulated expression of the proto-oncogene Myc in B cells and plasma cells. Myc-activating chromosomal translocations are the hallmark mutations of human Burkitt's lymphoma (BL) and mouse plasmacytoma (PCT). In the past fiscal year we have made significant advances in three project areas: We have demonstrated that mice bearing a mutated Myc gene controlled by reconstructed Ig light-chain loci (l or k) containing all elements required to establish locus control in vitro spontaneously develop B-cell lymphomas with histologic, cytologic, phenotypic, and molecular features resembling human BL. We have designated these tumors mouse Burkitt's lymphoma. We have shown that BALB/c mice harboring a human IL-6 transgene under the transcriptional control of the histocompatibility H2-Ld promoter spontaneously develop plasmacytomas. The tumors arise in gut-associated lymphoid tissues, contain Myc activating T(12;15) translocations, and are readily transplantable. Our finding suggests that the cooperation of the following three pathogenetic factors is crucial for PCT development in mice: constitutive IL-6 signaling (transgenic expression of IL-6), activation of Myc (chromosomal translocation), and PCT susceptibility alleles ( BALB/c genotype). We have established that the Myc-activating T(12;15) translocation in mice and the corresponding t(8;14) translocation in humans can be mimicked by gene insertion in mice. Insertion of Myc just upstream of Cm recreated the Cm-Myc recombination that is commonly found in human sporadic Burkitt's lymphoma and precursors of mouse plasmacytoma. Insertion of Myc 5' of Ca reproduced the type of Myc exchange that is most frequently observed in mature mouse plasmacytomas. The gene-targeted mice are prone to neoplastic B cell and plasma cell development, including plasmacytoma, follicular lymphoma, and diffuse large B cell lymphoma. The mice are currently used to study tumor progression mechanisms in B lineage cells and design new prevention and treatment approaches for Myc-dependent B cell and plasma cell tumors.
