c-IMycI-induced B cell and plasma cell neoplasms in mice

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We have continued our studies on the pathogenesis of mouse B cell and plasma cell neoplasms that are induced by chromosomal T(12;15) translocations that result in the deregulated expression of the proto-oncogene Myc (c-myc). The mouse T(12;15) translocation, the hallmark mutation of BALB/c plasmacytoma (PCT), is the direct counterpart of the human MYC-activating t(8;14)(q24;q32) translocation that is most commonly seen in human Burkitt lymphoma (BL). In the past fiscal year we have made significant advances in the following project areas: Using gene insertion in transgenic mice, we have successfully mimicked three different states of the human BL t(8;14)(q24;q32)/mouse PCT T(12;15) translocation. The newly developed strains were designated "iMyc." Our most recent work has shown that the iMyc-Em mice are prone to neoplastic B cell and plasma cell neoplasms, including lymphoblastic B-cell lymphoma (LBL), diffuse large B cell lymphoma (DLBCL) and plasmacytoma (PCT). Together these are tumors of mature B cells, which are of great relevance for B-cell derived non-Hodgkin's lymphomas in humans (Cancer Res. 65:1306-1315, 2005). Several lines of evidence indicate that the iMyc-Em mouse affords a good opportunity to design and test new approaches for the treatment and prevention of human B cell and plasma cell tumors. Because deregulated expression of MYC and BCL-XL are consistent features of the human plasma cell neoplasm, multiple myeloma (MM), we have investigated whether targeted expression of Myc and Bcl-XL in mouse plasma cells might lead to an improved mouse model of human MM. We crossed one of our newly developed iMyc strains, iMyc-Ca, with mice that contain a BCL-XL transgene driven by the mouse Igk 3' enhancer. Single transgenic BCL-XL mice remained tumor free by 380 days of age and single transgenic Myc mice developed B-cell tumors infrequently (9.3%). However, double transgenic Myc/BCL-XL mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). The tumors infiltrated the bone marrow and caused, in some cases, osteolytic lesions. These findings demonstrated that the enforced expression of Myc and BCL-XL by enhancers with peak activity in plasma cells generates tumors in mice that recapitulate key features of human MM (J. Clin. Invest. 113:1763-1773, 2004). In related cytogenetic work, we have studied the possible role of chromosome suprastructure on the origin of Myc-activating chromosomal translocations in mouse B-lineage cells. We investigated whether the location of Myc, Igh, and Igk on normal or Robertsonian fusion chromosomes affects Myc translocations and plasmacytoma (PCT) development in mice, but found that this was not the case. However, in Rb(6.15) mice, in which chromosomal inversions competed with chromosomal translocations for Igk-Myc juxtapositions, the former were found more frequently than the latter. This indicated, for the first time, that the spatial proximity of Igk and Myc in the interphase nucleus facilitates the illegitimate genetic rearrangement of these loci (Genes Chromosomes Cancer 42:416-426, 2005). Our findings suggest that Myc translocation-dependent mouse PCTs provide a good model system to advance our understanding of the relationship of higher-order genome organization, origin of chromosomal translocations, and development of cancer. We have further demonstrated that Myc-dependent peritoneal PCT in mice, the premier experimental model of inflammation-dependent plasma cell transformation, is useful to elucidate mechanisms of cancer prevention. In a study on the micronutrient selenium, we showed that selenium-depleted mice were totally refractory to PCT.