Insertional hypermutation in mineral oil‐induced plasmacytomas

Abstract

Unless stimulated by a chronic inflammatory agent such as mineral oil, plasma cell tumors are rare in young BALB/c mice. This raises the questions, What do inflammatory tissues provide to promote mutagenesis? and What is the nature of mutagenesis? We determined that mineral oil-induced plasmacytomas produce large amounts of endogenous retroelements—ecotropic and polytropic murine leukemia virus and intracisternal A-particles. Therefore, plasmacytoma formation might occur, in part, by de novo insertion of these retroelements, induced or helped by the inflammation. We recovered up to 10 de novo insertions in a single plasmacytoma, mostly in genes with common retroviral integration sites. Additional integrations accompany tumor evolution from a solid tumor through several generations in cell culture. The high frequency of de novo integrations into cancer genes suggests that endogenous retroelements are coresponsible for plasmacytoma formation and progression in BALB/c mice.

Biology and Diseases of Mice

“…Associated inflammation may promote retroelement insertion into cancer genes, thereby promoting tumors (Knittel et al, 2014). They can, however, be induced by intraperitoneal inoculation of granulomatogenic agents such as plastic filters, plastic shavings, or a variety of oils, particularly in BALB/c mice.…”

Infectivity and insertional mutagenesis of endogenous retrovirus in autoimmune NZB and B/W mice

“…Lysine-specific demethylases are known tumour suppressors. We also found an insertion in Fbxl10 (also known as lysine (K)-specific demethylase 2B, human orthologue KDM2B) in a plasmacytoma (Knittel et al, 2014).…”

“…Analogous to the B/W mice, which suffer from autoimmune disease and lymphadenopathy and eventually lymphoma , human systemic lupus erythematosus patients have a well-documented increased risk of non-Hodgkin's lymphoma (Bernatsky et al, 2005). As another example, BALB/ c mice injected with mineral oil suffer from inflammation and develop both a lupus-like disease (Satoh et al, 2003) and plasmacytomas, the latter of which (in addition to translocations) are driven by de novo insertions of endogenous MLV (Knittel et al, 2014). The increased susceptibility to cancer in autoimmune humans and mice could be solely due to the large number of proliferating cells, which are the targets of mutagenesis.…”

“…De novo MLV integration sites were recovered using the splinkerette approach (Mikkers et al, 2002), described in detail in Knittel et al (2014). Cellular DNA was restriction-digested with the enzymes Apo1, Nsp1 or Bst Y1 and ligated to a dsDNA oligonucleotide with a stable hairpin (splinkerette).…”

“…However, in the NS0/1 fusion partner, we identified other integration sites, which contributed to the tumorigenesis of the myeloma-derived cells (Knittel et al, 2014). Therefore, we considered the possibility that by generating hybridomas, we were studying subclones of the fusion partner, rather than the spleen cells themselves.…”