Aberrant V(D)J recombination is not required for rapid development of H2ax/p53-deficient thymic lymphomas with clonal translocations.
Histone H2AX is required to maintain genomic stability in cells and to suppress malignant transformation of lymphocytes in mice. H2ax(-/-)p53(-/-) mice succumb predominantly to immature alphabeta T-cell lymphomas with translocations, deletions, and genomic amplifications that do not involve T-cell receptor (TCR). In addition, H2ax(-/-)p53(-/-) mice also develop at lower frequencies B and T lymphomas with antigen receptor locus translocations. V(D)J recombination is initiated through the programmed induction of DNA double-strand breaks (DSBs) by the RAG1/RAG2 endonuclease. Because promiscuous RAG1/RAG2 cutting outside of antigen receptor loci can promote genomic instability, H2ax(-/-)p53(-/-) T-lineage lymphomas might arise, at least in part, through erroneous V(D)J recombination. Here, we show that H2ax(-/-)p53(-/-)Rag2(-/-) mice exhibit a similar genetic predisposition as do H2ax(-/-)p53(-/-) mice to thymic lymphoma with translocations, deletions, and amplifications. We also found that H2ax(-/-)p53(-/-)Rag2(-/-) mice often develop thymic lymphomas with loss or deletion of the p53(+) locus. Our data show that aberrant V(D)J recombination is not required for rapid onset of H2ax/p53-deficient thymic lymphomas with genomic instability and that H2ax deficiency predisposes p53(-/-)Rag2(-/-) thymocytes to transformation associated with p53 inactivation. Thus, H2AX is essential for suppressing the transformation of developing thymocytes arising from the aberrant repair of spontaneous DSBs.
Bassing
Craig H
CH
Howard Hughes Medical Institute, The Children's Hospital, Center for Blood Research, Institute for Biomedical Research, Department of Genetics, Harvard University Medical School, Boston, MA, USA.
Ranganath
Sheila
S
Murphy
Mike
M
Savic
Velibor
V
Gleason
Meagan
M
Alt
Frederick W
FW
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D003643:Death; D042822:Genomic Instability / Q000235:genetics; D006657:Histones / Q000172:deficiency* / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008677:Metaphase; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D045567:VDJ Recombinases / Q000235:genetics*
D004268:DNA-Binding Proteins; D006657:Histones; D016159:Tumor Suppressor Protein p53; D045567:VDJ Recombinases; C499308:Rag2 protein, mouse; C475961:gamma-H2AX protein, mouse