AID-deficient Bcl-xL transgenic mice develop delayed atypical plasma cell tumors with unusual Ig/Myc chromosomal rearrangements.
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.
Kovalchuk
Alexander L
AL
Laboratory of Cancer Biology and Genetics, Cancer Genomics Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
duBois
Wendy
W
Mushinski
Elizabeth
E
McNeil
Nicole E
NE
Hirt
Carsten
C
Qi
Chen-Feng
CF
Li
Zhaoyang
Z
Janz
Siegfried
S
Honjo
Tasuku
T
Muramatsu
Masamichi
M
Ried
Thomas
T
Behrens
Timothy
T
Potter
Michael
M
D000818:Animals; D003564:Cytidine Deaminase / Q000172:deficiency* / Q000235:genetics; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin; D016259:Genes, myc; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054219:Neoplasms, Plasma Cell / Q000235:genetics* / Q000517:prevention & control; D051020:bcl-X Protein / Q000172:deficiency* / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase