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+BclXL 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 chromnosomal 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 pristane 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.
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