Myc-activating chromosomal translocations

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Chromosomal translocations that deregulate the Myc proto-oncogene by juxtaposition to regulatory sequences of immunoglobulin (Ig) heavy- or light chain genes are the hallmark mutations of human Burkitt's lymphoma (BL) and mouse plasmacytoma (PCT). In the past fiscal year, we have continued our studies on Myc-activating chromosomal translocations in B cells and have made significant advances in three major projects. (i) We have found that mice bearing a mutated Myc gene controlled by reconstructed Ig light-chain loci (l/Myc or k/Myc) 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 BL. (ii) We have further demonstrated that BALB/c plasmacytoma-typical 12;15 translocations can be mimiced by inserting Myc into the Ig heavy-chain locus, either upstream of Cm or upstream of Ca. The former gene insertion recreates the plasmacytoma precursor-typical Cm/Myc recombination, the latter reproduces the type of Myc recombination that is most frequently observed in mature plasmacytomas (Ca/Myc recombination). Numerous gene-targeted Cm/Myc and Ca/Myc mice have already developed B-cell neoplasia, including PCTs, follicular lymphomas, and diffuse large cell lymphomas. The biological and molecular characterization of these tumors is the focus of ongoing studies. (iii) We have shown that transplantable plasmacytomas harboring Myc-activating 12;15 translocations develop at high frequency in lymphoid tissues (Peyer's patches and lymph nodes) of untreated (no pristane) BALB/c mice congenic for a human IL-6 transgene under the transcriptional control of the histocompatibility H-2Ld promoter. This finding is a breakthrough in experimental PCT research because it suggests that the cooperation of three pathogenetic factors suffices to trigger PCT development in mice: constitutive IL-6 signaling (transgenic expression of IL-6), activation of Myc (12;15 translocation), and PCT susceptibility alleles (BALB/c genotype).