A Novel Mechanism of Ig and Myc Translocations in AID-Deficient Mice.

Abstract

Consistent with the role of activation induced cytidine deaminase (AID) as a major “catalyst” of aberrant translocations between the Ig switch regions and c-myc, AID-sufficient Bcl-xL transgenic mice rapidly develop transplantable plasmacytomas with classical T(12;15) translocations. Unexpectedly, we found that Bcl-xL transgenic BALB/cAn mice deficient for AID (designated pBxAicda−/− mice) also developed plasma cell tumors but with a lower frequency (24% vs. 62%) and with a longer mean latency (108 d vs. 36 d) than AID-sufficient controls. Six out of nine of primary tumors were shown by interphase FISH to contain a T(12;15) translocation and one other had a T(6;15). pBxAicda−/− tumors did not transplant well because they were presumably in early stages of neoplastic development or had not progressed to full malignancy including association with ascites. Nevertheless, two tumors (4885 and 4961) were successfully transplanted and established as stable cell lines. They exhibited mature plasma cell phenotype (CD45−, CD138+, PC-1+, CD19−, CD23−) and secreted IgM. Gene expression profiling showed no significant difference from control plasma cell tumors of AID-sufficient mice. Detailed molecular and cytogenetic analysis of 4885 uncovered an unusual unbalanced T(12;15) translocation with IgH Cμ and Pvt-1 in a head to tail orientation at the breakpoint, resulting in elevated c-myc expression as detected by qPCR. In contrast, 4961, a T(12;15) negative cell line, had elevated N-myc expression as a result of paracentric inversion of Chr. 12. These rearrangements had no direct association with RAG activity. We conclude that rapid development of malignant plasma cell tumors with reciprocal T(12;15) does require AID, and that in AID deficiency a novel less efficient mechanism can be utilized to bring c-myc and Ig genes into juxtaposition.