title: 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.affiliation: Laboratory of Cancer Biology and Genetics, Cancer Genomics Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Kovalchuk
authors.forename: Wendy
authors.initials: W
authors.lastname: duBois
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mushinski
authors.forename: Nicole E
authors.initials: NE
authors.lastname: McNeil
authors.forename: Carsten
authors.initials: C
authors.lastname: Hirt
authors.forename: Chen-Feng
authors.initials: CF
authors.lastname: Qi
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Li
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Masamichi
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Timothy
authors.initials: T
authors.lastname: Behrens
authors.forename: Michael
authors.initials: M
authors.lastname: Potter
mesh_terms: 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)
chemical_list: C494812:Bcl2l1 protein, mouse; D051020:bcl-X Protein; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase