A transgenic mouse model of plasma cell malignancy shows phenotypic, cytogenetic, and gene expression heterogeneity similar to human multiple myeloma.

University of Minnesota, Minneapolis, Minnesota 55455, USA.
Cancer Research (Impact Factor: 9.28). 06/2007; 67(9):4069-78.
Source: PubMed

ABSTRACT Multiple myeloma is an incurable plasma cell malignancy for which existing animal models are limited. We have previously shown that the targeted expression of the transgenes c-Myc and Bcl-X(L) in murine plasma cells produces malignancy that displays features of human myeloma, such as localization of tumor cells to the bone marrow and lytic bone lesions. We have isolated and characterized in vitro cultures and adoptive transfers of tumors from Bcl-xl/Myc transgenic mice. Tumors have a plasmablastic morphology and variable expression of CD138, CD45, CD38, and CD19. Spectral karyotyping analysis of metaphase chromosomes from primary tumor cell cultures shows that the Bcl-xl/Myc tumors contain a variety of chromosomal abnormalities, including trisomies, translocations, and deletions. The most frequently aberrant chromosomes are 12 and 16. Three sites for recurring translocations were also identified on chromosomes 4D, 12F, and 16C. Gene expression profiling was used to identify differences in gene expression between tumor cells and normal plasma cells (NPC) and to cluster the tumors into two groups (tumor groups C and D), with distinct gene expression profiles. Four hundred and ninety-five genes were significantly different between both tumor groups and NPCs, whereas 124 genes were uniquely different from NPCs in tumor group C and 204 genes were uniquely different from NPCs in tumor group D. Similar to human myeloma, the cyclin D genes are differentially dysregulated in the mouse tumor groups. These data suggest the Bcl-xl/Myc tumors are similar to a subset of plasmablastic human myelomas and provide insight into the specific genes and pathways underlying the human disease.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are useful imaging modalities for evaluating tumor progression and treatment responses in genetically engineered mouse models of solid human cancers, but the potential of integrated FDG-PET/CT for assessing tumor development and new interventions in transgenic mouse models of human blood cancers such as multiple myeloma (MM) has not been demonstrated. Here we use BALB/c mice that contain the newly developed iMyc(ΔEμ) gene insertion and the widely expressed H2-L(d)-IL6 transgene to demonstrate that FDG-PET/CT affords an excellent research tool for assessing interleukin-6- and MYC-driven plasma cell tumor (PCT) development in a serial, reproducible and stage- and lesion-specific manner. We also show that FDG-PET/CT permits determination of objective drug responses in PCT-bearing mice treated with the investigational proteasome inhibitor ixazomib (MLN2238), the biologically active form of ixazomib citrate (MLN9708), that is currently in phase 3 clinical trials in MM. Overall survival of 5 of 6 ixazomib-treated mice doubled compared with mice left untreated. One outlier mouse presented with primary refractory disease. Our findings demonstrate the utility of FDG-PET/CT for preclinical MM research and suggest that this method will play an important role in the design and testing of new approaches to treat myeloma.
    Blood Cancer Journal 11/2013; 3:e165. · 2.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Plasma cell neoplasms comprise a spectrum of diseases that include monoclonal gammopathy of undetermined signifi-cance (MGUS) and multiple myeloma (MM). Flow cytometric immunophenotyping has become an invaluable tool as an ancillary and diagnostic test for hematologic malignancies and is being used with increasing frequency in the diag-nosis and monitoring of plasma cell neoplasms. As multiparameter flow cytometry has evolved, faster fluidics and de-tection systems facilitate the screening of a large number of events and the detection of multiple antigens simultane-ously. This review addresses the approaches used to evaluate clonal plasma cell neoplasms and describes different sur-face and cytoplasmic markers and techniques that are important for the study of these diseases.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mice susceptible to plasma cell tumors provide a useful model for human multiple myeloma. We have shown previously that mice expressing an Eμ-v-abl oncogene develop solely plasmacytomas. Here we show here that loss of the pro-apoptotic BH3-only protein Bim or, to a lesser extent, over-expression of anti-apoptotic Bcl-2 or Mcl-1, significantly accelerated the development of plasmacytomas and increased their incidence. Disease was preceded by an increased abundance of plasma cells, presumably reflecting their enhanced survival capacity in vivo. Plasmacytomas of each genotype expressed high levels of v-abl and frequently harboured a rearranged c-myc gene, probably as a result of chromosome translocation. As in human multiple myelomas, elevated expression of cyclin D genes was common and p53 deregulation rare. Our results for plasmacytomas highlight the significance of anti-apoptotic changes in multiple myeloma, which include elevated expression of Mcl-1 and, less frequently, Bcl-2, and suggest that closer attention to defects in Bim expression is warranted.
    Blood 07/2014; · 9.78 Impact Factor

Full-text (2 Sources)

Available from
May 29, 2014