Aberrant V(D)J recombination is not required for rapid development of H2ax/p53-deficient thymic lymphomas with clonal translocations

Abstract

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 αβ 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.