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Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice
Wan Cheung Cheung, … , Roberto D. Polakiewicz, Siegfried Janz
Wan Cheung Cheung, … , Roberto D. Polakiewicz, Siegfried Janz
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1763-1773. https://doi.org/10.1172/JCI20369.
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Article Oncology

Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice

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Abstract

Deregulated expression of both Myc and Bcl-XL are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-XL in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, MycHis, into the mouse Ig heavy-chain Cα locus. We also generated Bcl-XL transgenic mice that contain a multicopy Flag-tagged mouse Bcl-xFlag transgene driven by the mouse Ig κ light-chain 3′ enhancer. Single-transgenic Bcl-XL mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-XL mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of MycHis and Bcl-XLFlag proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-XL mice. Our findings demonstrate that the enforced expression of Myc and Bcl-XL by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma.

Authors

Wan Cheung Cheung, Joong Su Kim, Michael Linden, Liangping Peng, Brian Van Ness, Roberto D. Polakiewicz, Siegfried Janz

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Figure 6

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Myc/Bcl-XL PCNs infiltrate the bone marrow, produce monoclonal Ig, and c...
Myc/Bcl-XL PCNs infiltrate the bone marrow, produce monoclonal Ig, and cause osteolytic lesions. (A) Bone marrow infiltration with Igκ-producing neoplastic plasma cells (original magnification, _63). (B) Palisades of neoplastic plasma cells (brown) destroying the luminal face of a femur’s corticalis (IgG immunostaining; original magnification, _40). Two bone resorption lacunae are denoted by arrows. (C) Radiographs of large osteolytic lesion with apparent pathological fracture (1, left humerus), osteolytic lesion without fracture (2, right femur), and hairline fracture without visible osteolytic lesion (3, left forearm). (D) Protein electropherogram of serum and peritoneal lavage samples containing M-spikes (red arrows) isotyped using ELISA (bottom). (E) Frequency and type of mutations in the 3′ JH4 region of rearranged variable (V) genes. Shown at the top is a scheme of the mouse Igh locus. PCR primers J558 and JH4 were used to amplify rearranged VDJ genes and linked 3′JH4 sequences. Sequencing primers iJH4-5′ and iJH4-3′ were used to detect mutations in the 344-bp 3′ JH4 region. Shown in the center are bar diagrams of the number of mutations in the 3′ JH4 region in PCNs and plasmablasts from tumor-free Myc/Bcl-XL mice (PB, left panel). The corresponding mutation frequencies (mutations/3440 bp) are plotted to the right. Shown at the bottom are types and occurrences of base substitution mutations in the 3′ JH4 region of rearranged VH genes in PCN and PB. The tumor sample also contained a deletion, δT. The location of the mutation in the 3′ JH4 regions is depicted in Supplemental Figure 6.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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