AID-deficient Bcl-xL transgenic mice develop delayed atypical plasma cell tumors with unusual Ig/Myc chromosomal rearrangements.

Abstract

Activation-induced cytidine deaminase (AID) is required for immunoglobulin (Ig) class switch recombination and somatic hypermutation, and has also been implicated in translocations between Ig switch regions and c-Myc in plasma cell tumors in mice. We asked if AID is required for accelerated tumor development in pristane-treated Bcl-xL transgenic BALB/c mice deficient in AID (pBxAicda-/-). pBxAicda-/- mice developed tumors with a lower frequency (24 vs. 62%) and a longer mean latency (108 vs. 36 d) than AID-sufficient mice. The tumors appeared in oil granuloma tissue and did not form ascites. By interphase fluorescence in situ hybridization, six out of nine pBxAicda-/- primary tumors had T(12;15) and one had T(6;15) chromosomal translocations. Two tumors were transplantable and established as stable cell lines. Molecular and cytogenetic analyses showed that one had an unusual unbalanced T(12;15) translocation, with IgH Cmu and Pvt-1 oriented head to tail at the breakpoint, resulting in an elevated expression of c-Myc. In contrast, the second was T(12;15) negative, but had an elevated N-Myc expression caused by a paracentric inversion of chromosome 12. Thus, novel mechanisms juxtapose Ig and Myc-family genes in AID-deficient plasma cell tumors.

• Authors: Alexander L Kovalchuk, Wendy duBois, Elizabeth Mushinski, Nicole E McNeil, Carsten Hirt, Chen-Feng Qi, Zhaoyang Li, Siegfried Janz, Tasuku Honjo, Masamichi Muramatsu, Thomas Ried, Timothy Behrens, Michael Potter
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 204 Issue 12 Pg. 2989-3001 (Nov 26 2007) ISSN: 1540-9538 [Electronic] United States
• PMID: 17998390 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Bcl2l1 protein, mouse
• bcl-X Protein
• AICDA (activation-induced cytidine deaminase)
• Cytidine Deaminase

Topics

• Animals
• Cytidine Deaminase (deficiency, genetics)
• Gene Rearrangement
• Genes, Immunoglobulin
• Genes, myc
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• Mice, Transgenic
• Neoplasms, Plasma Cell (genetics, prevention & control)
• bcl-X Protein (deficiency, genetics)