New models of plasmacytomagenesis in mice have been developed that substantially condense the latent period from 200+ days to 80 days. This potentially permits identifying the precursor cells and, possibly, early stages in the process. Transgenic N18 BALB/cAnPt-H-2Ld-hu-IL-6 (IL-6 Tg) heterozygotes at N18 were crossed to heterozygous N6 BALB/cAnPt-SV-bclXL (SV-bclXL Tg) to generate IL-6/+,BclXL/+ double transgenic (dTg) progeny. Ninety-one percent of the mice carrying both transgenes developed plasma cell tumors (PCTs) at a mean age of 89 days. In contrast, 53% of the BALB/c (B/c)-IL-6 mice developed PCTs at a mean age of 301 days, and 12% of the SV-bclXL mice developed PCTs with a mean age of 433 days. The dTg PCTs developed predominantly in mucosal associated lymphoid tissues, the Peyer's patches (PP), mesenteric lymph node (MLN) and lamina propria of the small intestine. The IL-6 and IL/6+Bc1XL dTg mice developed striking accumulations of plasma cells i.e. plasma cell hyperplasia (PCH) that accumulate in the medullary cords of lymph nodes. The earliest morphological evidence of B-cell accumulation occurs in germinal centers in PP and MLN that become heavily populated by lymphocytes. Emigrants from GCs give rise to proliferating plasmablastic cells that migrate into paracortical and medullary cords. In peripheral lymph nodes the plasma cells become mature by having small nuclear areas as determined by the Image J program. Early PCT tumors develop in the medullary cords of MLN and in the contiguous lamina propria of PP. Further clues on the B cell origin of PCTs have been provided by the antigen binding activities of the monoclonal (myeloma) proteins they produce. About 40% of the PCTs bind to dsDNA and a proportion of these are polyreactive with irrelevant exogenous and endogenous antigens suggesting that B cells with low affinities that enter GCs are more prone to undergoing neoplastic transformation. Expansion of the late B-cell population in GCs leads to the development of C-myc activation chromosomal translocations (CTs). A high percentage of dTg PCTs have t(12;15) CTs. This process may be AID dependent and we are currently attempting to induce PCTs in AID-/- mice. Thus far evidence in the literature indicates AID activity ceases in plasma cells , further implicating the GC B- cell populations as the cells in which CTs occur. The molecular basis for IL-6/BclXL cooperation is not established but may be due to a proliferative action of IL-6 on a pre-plasmablast cell that is co-stimulated by available antigens. B-cells with Myc activating CTs are expanded and develop additional mutations or epigenetic changes leading to more autonomous proliferation.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005596-36
Application #
7289388
Study Section
(LG)
Project Start
Project End
Budget Start
Budget End
Support Year
36
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Casellas, Rafael; Yamane, Arito; Kovalchuk, Alexander L et al. (2009) Restricting activation-induced cytidine deaminase tumorigenic activity in B lymphocytes. Immunology 126:316-28
Potter, Michael (2007) The early history of plasma cell tumors in mice, 1954-1976. Adv Cancer Res 98:17-51
Park, Eun Sung; Shaughnessy Jr, John D; Gupta, Shalu et al. (2007) Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia. BMC Genomics 8:302
Kim, Byung-Gyu; Li, Cuiling; Qiao, Wenhui et al. (2006) Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441:1015-9
Potter, Michael (2003) Neoplastic development in plasma cells. Immunol Rev 194:177-95
Janz, Siegfried; Potter, Michael; Rabkin, Charles S (2003) Lymphoma- and leukemia-associated chromosomal translocations in healthy individuals. Genes Chromosomes Cancer 36:211-23
Potter, M; Jones, G; Dubois, W et al. (2000) Myeloma proteins that bind Hsp65 (GroEL) are polyreactive and are found in high incidence in pristine induced plasmacytomas. Curr Top Microbiol Immunol 252:265-71
Potter, M; Melchers, F (2000) Opinions on the nature of B-1 cells and their relationship to B cell neoplasia. Curr Top Microbiol Immunol 252:307-24
Potter, M (1999) Indomethacin inhibition of pristane plasmacytomagenesis in genetically susceptible inbred mice. Adv Exp Med Biol 469:151-6
Potter, M; Wax, J S; Hansen, C T et al. (1999) BALB/c.CBA/N mice carrying the defective Btk(xid) gene are resistant to pristane-induced plasmacytomagenesis. Int Immunol 11:1059-64

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