Myc-activating chromosomal translocations

点击翻译按钮获取中文摘要

We have continued our studies on chromosomal translocations that deregulate the Myc proto-oncogene in B cells after juxtaposition to regulatory sequences of immunoglobulin (Ig) heavy- or light-chain genes. 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: (i) We have found 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. (ii) We have demonstrated that the BALB/c plasmacytoma-typical 12;15 translocation can be mimicked by inserting Myc into the Ig heavy-chain locus. Insertion of Myc upstream of Cm recreated the plasmacytoma precursor-typical Cm/Myc recombination, while insertion of Myc 5' of Ca reproduced the type of Myc exchange that is most frequently observed in mature plasmacytomas (Ca/Myc recombination). We demonstrated that gene-targeted Cm/Myc mice and Ca/Myc mice are prone to developing B-cell neoplasms, including plasmacytoma, follicular lymphoma, and diffuse large cell lymphoma. 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 spontaneously in lymphoid tissues of untreated (no pristane) BALB/c mice harboring a human IL-6 transgene under the transcriptional control of the histocompatibility H2-Ld promoter. This finding indicated that the cooperation of three pathogenetic factors is crucial for 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).