Mouse Model of MYC-Deregulating Chromosomal Translocations Associated with Human Burkitt Lymphoma and Multiple Myeloma.

Purpose: Burkitt lymphoma (BL) is tightly associated with chromosomal t(8;14)(q24;q32) translocations that result in the deregulated expression of the MYC (c-myc) oncogene due to its juxtaposition to enhancers of the immunoglobulin-heavy chain locus IGH. The t(8;14)(q24;q32) MYC-IGH translocation is widely believed to be the initiating event in the pathogenesis of BL. Multiple myeloma (MM) is a malignant neoplasm of plasma cells that is often associated with complex cytogenetic alterations that juxtapose MYC, analogous to the t(8;14)(q24;q32) translocation, to IGH enhancers. However, MYC-IGH rearrangements of this sort occur during the progression of MM, not as tumor-initiating events as in BL. Accurate mouse models of MYC deregulation associated with human BL and MM are needed to study the events involved in tumor initiation and progression and design new approaches for treatment and prevention. To that end, we have generated a new mouse model of human t(8;14)(q24;q32) translocation.

Experimental procedure: We inserted a His₆-tagged mouse Myc cDNA, Myc^His, into two different locations of the mouse immunoglobulin heavy-chain locus, Igh, just 5′ of Eμ or Cμ. In the latter case, Eμ was deleted during gene targeting. The newly developed gene-insertion strains were designated iMyc^Eμ and iMyc^Cμ. The iMyc^Eμ mice provide a specific model of the t(8;14)(q24;q32) observed in endemic BL (eBL). The iMyc^Cμ mice mimic the t(8;14)(q24;q32) found in sporadic BL (sBL) and immunodeficiency-associated BL (iBL) (Fig. 1).

Figure 1

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Figure 1

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Result: Both “iMyc” gene-insertion strains are prone to the spontaneous development of mature B cell and plasma cell tumors. However, in the Eμ-containing iMyc^Eμ mice, tumors arose earlier and tumor incidence was higher compared to the Eμ-deleted iMyc^Cμ (Fig. 2 left).

Figure 2

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This correlated well with the control of Myc^His expression by Eμ, as Myc^His mRNA levels were higher in B cells from iMyc^Eμ than iMyc^Cμ mice. Interestingly, the iMyc^Cμ transgene was as effective in inducing inflammation-dependent peritoneal plasmacytomas as the iMyc^Cμ transgene (Fig. 2 right). This indicated that host factors, such as chronic inflammation, can greatly enhance the transformation-inducing potency of a deregulated Myc gene that is only weakly oncogenic in spontaneous tumor development.

Conclusion: The “iMyc” mice provide a model of Myc deregulation that is conducive to plasma cell tumors in mice. The mice may thus afford a good opportunity to identify the genes that collaborate with Myc in neoplastic plasma cell development. Combined with the transgenic expression of MM genes, such as DKK1, the “iMyc” mice may also be useful as a platform for modelling human plasma cell neoplasms in mice.