Transgenic Mouse Modeling of Therapeutic Responses in Myeloma

While myeloma is still considered a fatal disease, new therapeutic approaches, including combination of drugs that target different intracellular pathways, have shown marked improvements in response and survival. Yet there are wide variations in responses seen in the patient population. One major source is the variation in chromosomal abnormalities and the genes deregulated among the plasma cell (PC) tumors. Another may be in inherited variations (SNPs) that can have a major influence on drug distribution, transport and metabolism. Our laboratory has developed a transgenic mouse model targeting overexpression of c-myc and bcl-xL in late B cells, that results in early expansion of non-malignant PCs, followed by development of clonal plasma cell malignancies in 100% of the mice. We have reported on cell surface, chromosomal abnormalities, and gene expression profiles of the mouse plasma cell tumors, that demonstrate a very similar profile and heterogeneity to human myelomas. The mouse PC tumors can be adoptively transferred to syngenic recipient mice, as well as grown in culture. The advantage of this model is that the impact of tumor heterogeneity can be assessed in a common germline genetic background in the mice; and an intact immune system is maintained, unlike many common xenograft models. We find that disease progression is variable among tumors and have extended this observed heterogeneity of progression to analysis of drug sensitivity; for example, identifying tumors that are highly sensitive to dexamethasone, and others extremely resistant, and others that show protection in the presence of IL-6. Although bcl-xL expression is important in the initiation of the transgenic malignancy, it was not clear if Bcl-xL was required to maintain the transformed phenotype. To test this, we blocked Bcl-xL with the inhibitor BH3I-2′(Calbiochem). We find that inhibition of Bcl-xL is effective in killing the PC tumors in vitro, and dose is directly related to levels of bcl-xL expression. We also examined various dose combinations of dexamethasone and BH3I-2′ and found an antagonistic relationship of the two drugs. We are in the process of expanding the tumor mouse population to target other therapeutic approaches in the transgenic mouse that models tumor heterogeneity in a common genetic background.