Figure 6: Mouse models of human WM. (a) Xenotransplantation models rely on the propagation of human WM cells in SCID mice that may contain human bone (blue) as a nesting ground for incoming tumor cells. (b) Three examples of strains of mice that are prone to WM-like tumors. Tumor development in NSF.V+ mice is dependent on insertional somatic mutagenesis affected by an infectious ecotropic murine leukemia virus. See Section 6.3 for details. (c) Generation of strain C.IL6/BCL2/ mice, an IWMF-sponsored project in the laboratory of the author of this paper. The compound transgenic mouse strain combines two independently developed oncogenes, H2--IL6 (hereafter called IL6) and EμSV-Bcl-2-22 (hereafter called BCL2), on the genetic background of AID-deficient BALB/c (c) mice. Strain C is uniquely susceptible to late-stage B cell and plasma cell tumors [219, 220] due to a complex genetic trait that includes hypomorphic (weak efficiency) alleles of genes encoding the cell-cycle inhibitor, , and the FKBP12 rapamycin-associated protein, Frap , and the absence of the interferon-inducible gene, Mndal . The scientific rationale for using the IL6 transgene is strong and includes the following considerations. IL-6 is a pro-inflammatory cytokine that impacts many blood cancers , including Hodgkin lymphoma , non-Hodgkin lymphoma  and myeloma [227, 228]. In human WM, IL-6 has long been recognized as a major growth, differentiation, and survival factor. In mice, IL-6 is firmly linked to inflammation-dependent plasmacytoma (PCT) induced by i.p. injection of pristane . This treatment provokes the formation of inflammatory granulomas, a rich source of IL-6 at the site of tumor development . Critical evidence for the involvement of IL-6 in inflammation-induced PCT was first obtained in studies with C mice, showing that tumor growth is enhanced by exogenous IL-6 but inhibited by antibodies to IL-6 or its receptor . Subsequent work demonstrated that C mice homozygous for a null allele of IL6 are resistant to both inflammation-induced PCT  and Myc/Raf retrovirus-accelerated PCT . Conversely, C mice carrying the IL6 transgene develop PCT spontaneously without a requirement peritoneal inflammation . The scientific rationale for using the BCL2 transgene is equally compelling. Enforced expression of the BCL-2 death repressor  increases the apoptotic threshold for tumor precursors because BCL-2 blocks many death signals during normal B cell development [236, 237]; cooperates with oncogenes in vitro to promote mitogen-independent cell survival ; and accelerates oncogene-driven B-lymphoma in vivo [239, 240]. Previous work with BCL2 transgenic mice and a highly similar transgene [241, 242] showed that BCL-2 selects B cells harboring deregulated oncogenes for tumor development [243, 244]. BCL2 overexpression keeps alive B cells that would normally be eliminated due to developmental problems , autoreactivity , dysfunctional BCR , or illegitimate genetic rearrangements . Loss of AID will modify BCL2/IL6-driven tumor development such that only IgM+ tumors can arise; this is because AID is essential for class switch recombination (CSR) [249, 250]. AID is encoded by Aicda; it deaminates DNA cytidine to uracil residues, which results in U:G mismatches . Tumor induction studies using AID−/− mice that carry IL6 or Bclx transgenes have been performed [252–254], indicating that the ongoing approach using C.IL6/BCL2/ mice should be similarly successful.