Tissue Origin of Igh/Myc Chromosomal Translocations in An Accelerated Pristane-Induced Plasma Cell Tumor Model using BALB/C-Bcl-Xl Transgenic Mice and the Inhibitory Effects of Defective Genes Governing Class Switch recombination in Ung and Aicda Knockout Mice.

Plasma cell tumors (PCT) can be induced by the intraperitoneal injection of BALB/cAn (B/c) mice with a poorly metabolized minearal oil such as pristane. Pristane causes the formation of a robust chronic inflammatory tissue resulting in oil granulomas (OG) in which the PCTs develop. The emerging transplantable PCTs usually can be diagnosed in Wright-Giemsa stained cytofuge preparations beginning around 120 days and continuing over the next 8–10 months. Induction is greatly accelerated in BALB/c-BclxL (B/cXL) transgenic (Tg) mice with PCTs first appearing around day 40 and >80% of the mice developing PCTs by day 100. About 80% of pristane-induced PCTs in both B/c and B/cXL mice have T(12;15) translocations that deregulate Myc expression, which appears to be the dominant and possibly the initiating step in PCT development. We have been studying the early stages of PCT development and have found an intriguing new precursor step in the form of aggregates of B220+ lymphocytes. By day 7 post pristane, OG on the mesenteries of the small intestine can have from 10–30 of these aggregates, each containing from 50 to 1000 B lymphocytes. 40–70% of these aggregates in the OG are associated with plasma cells (PC) ranging from 30 to 200 in number. Mitotic figures were not seen in lymphocytes, although 2–8% of them are Ki-67+ or incorporate BrdU, suggesting they are becoming activated for cycling. In contrast, a much higher proportion of the associated PCs (~29%) are Ki-67+ and some of these have mitotic figures. These PC have a mature appearance and include varying proportions of Mott cells. Electron microscopic studies have revealed transitions from lymphocytes to PC in these extramedullary plasmacytopoietic sites. We have previously described focal proliferations of atypical PCs in the OG that appear to be a direct precursor of the PCT. These atypical PCs resemble those in most primary transplantable PCTs. We have studied precursor stages of plasmacytomagenesis for the evidence of Igh/C-Myc T(12;15). Most atypical foci and a few plasma cells associated with lymphoid aggregates as early as day 14 after pristane injection were positive for T(12;15) by FISH. Genetic defects in critical elements of class switch recombination (CSR), AID and UNG, can interfere with PCT development by reducing switch region-dependent translocations. Both deficiencies result in the absence of classical IgH switch regionc-Myc translocations detectable by PCR (Ramiro, Nature 440, 105–109, 2006 and our observations). Aicda−/− B/cXL Tg+ are defective in CSR but only partially resistant to PCT induction. They can develop T(12;15) without switch region participation. In contrast, Ung-defective mice undergo reduced CSR by the alternative Msh2 pathway but Ung−/− Bcl-xL Tg+ mice are highly resistant to PCT induction by pristane.