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). 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 PCTs developed predominantly in mucosal associated lymphoid tissues, the Peyer's patches, mesenteric lymph node and lamina propria of the small intestine. The IL-6 and IL/6+Bc1XL double transgenic mice developed striking accumulations of plasma cells that disrupted medullary and paracortical cords of lymph nodes. The source of the PCT precursor cells appeared to be proliferating plasmablastic cells of follicular origin that migrated into paracortical and medullary cords. Thus far, five out of six of the PCTs carry the myc activating and deregulating chromosomal translocation t (12;15). These accelerated model systems of PCT development in lymphoid tissues will facilitate characterization of preneoplastic states and identification of genetic changes that lead to plasma cell neoplasia. When bclXL Tg mice are given pristine i.p., one to two focal plasma cell proliferations (foci) can be identified 14 days later. In collaboration with Siegfried Janz we have given pristane to mice in which a c-myc locus has been inserted into chromosome 12. These mice develop multiple foci in 14 days, and the oil granuloma is nearly populated with plasma cells. In both systems these lesions can be found around a month or more before the mice develop aggressive tumors. We are beginning to explore the characteristics of these preneoplastic populations. We continue experiments designed to identify genes that determine susceptibility to plasma cell tumor formation.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005596-35
Application #
7038578
Study Section
(LG)
Project Start
Project End
Budget Start
Budget End
Support Year
35
Fiscal Year
2004
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

Showing the most recent 10 out of 11 publications