Pig IgM

The immunoglobulin genes have not been genetically characterized as thoroughly in cattle as in other mammals, particularly humans and mice. Comparative gene mapping in mammals suggests that the bovine immunoglobulin heavy chain genes, IGHG4 and IGHM might be syntenic with the FOS oncogene. Interestingly, however, when these genes were assigned to bovine syntenic groups utilizing a panel of bovine: hamster hybrid somatic cells, IGH genes were shown to be syntenic with the FES oncogene rather than FOS. In this study IGH and FES were assigned to Bos taurus chromsome 21 while FOS was assigned to chromosome 10. In addition, bovine-specific immunoglobulin-like sequences were observed in the hybrid somatic cells, and one, IGHML1, was mapped to bovine syntenic group U16. The probes used for somatic-cell mapping were also used to screen a small number of cattle of several different breeds for restriction fragment length polymorphisms. IGHG4 and IGHM were shown to be highly polymorphic, while FOS and FES were not.

The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin mu (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysis-targeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.