Cellular context-dependent effects of H2ax and p53 deletion on the development of thymic lymphoma.
H2AX and Artemis each cooperate with p53 to suppress lymphoma. Germline H2ax(-/-)p53(-/-) mice die of T-cell receptor-β(-) (TCR-β(-)) thymic lymphomas with translocations and other lesions characteristic of human T-cell acute lymphoblastic leukemia. Here, we demonstrate that mice with inactivation of H2ax and p53 in thymocytes die at later ages to TCR-β(-) or TCR-β(+) thymic lymphomas containing a similar pattern of translocations as H2ax(-/-)p53(-/-) tumors. Germline Artemis(-/-) p53(-/-) mice die of lymphomas with antigen receptor locus translocations, whereas Artemis(-/-)H2ax(-/-)p53(-/-) mice die at earlier ages from multiple malignancies. We show here that Artemis(-/-) mice with p53 deletion in thymocytes die of TCR-β(-) tumors containing Tcrα/δ translocations, other clonal translocations, or aneuploidy, as well as Notch1 mutations. Strikingly, Artemis(-/-) mice with H2ax and p53 deletion in thymocytes exhibited a lower rate of mortality from TCR-β(-) tumors, which harbored significantly elevated levels of genomic instability. Our data reveal that the cellular origin of H2ax and p53 loss impacts the rate of mortality from and developmental stage of thymic lymphomas, and suggest that conditional deletion of tumor suppressor genes may provide more physiologic models for human lymphoid malignancies than germline inactivation.
Yin
Bu
B
Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Yang-Iott
Katherine S
KS
Chao
Linda H
LH
Bassing
Craig H
CH
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D004720:Endonucleases; D005434:Flow Cytometry; D042822:Genomic Instability; D006657:Histones / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008223:Lymphoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D013953:Thymus Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D004720:Endonucleases; D006657:Histones; D009687:Nuclear Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016159:Tumor Suppressor Protein p53; C473337:Dclre1c protein, mouse; C475961:gamma-H2AX protein, mouse