Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations.
Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR beta gene enhancer (E beta) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the E beta mutation into p53-/- mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses.
Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Brian B
BB
Haines
Chun Jeih
CJ
Ryu
Sandy
S
Chang
Alexei
A
Protopopov
Andreas
A
Luch
Yun Hee
YH
Kang
Dobrin D
DD
Draganov
Maria F
MF
Fragoso
Sang Gi
SG
Paik
Hyo Jeong
HJ
Hong
Ronald A
RA
DePinho
Jianzhu
J
Chen
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D017384:Sequence Deletion / Q000235:genetics; D032681:Spectral Karyotyping; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D016159:Tumor Suppressor Protein p53