Chimeric IgH-TCR/ translocations in T lymphocytes mediated by RAG

TY - JOUR

T1 - Chimeric IgH-TCR/ translocations in T lymphocytes mediated by RAG

AU - Callén, Elsa

AU - Bunting, Sam

AU - Huang, Ching Yu

AU - Difilippantonio, Michael J.

AU - Wong, Nancy

AU - Khor, Bernard

AU - Mahowald, Grace

AU - Kruhlak, Michael J.

AU - Ried, Thomas

AU - Sleckman, Barry P.

AU - Nussenzweig, André

N1 - Funding Information: We thank Joseph Cheng for help with the image analysis system and for comments on the manuscript. This work is supported in part by the Intramural research Program of the NIH, National Cancer Institute, Center for Cancer Research. B.S. is supported by NIH grant AI074953. The authors declare no financial conflict of interest.

PY - 2009/8/1

Y1 - 2009/8/1

N2 - Translocations involving the T cell receptor alpha/delta (TCRα/δ) chain locus, which bring oncogenes in the proximity of the TCRα enhancer, are one of the hallmark features of human T cell malignancies from ataxia telangiectasia (AT) and non-AT patients. These lesions are frequently generated by the fusion of DNA breaks at the TCRα/δ locus to a disperse region centromeric of the immunoglobulin heavy chain (IgH) locus. Aberrant VDJ joining accounts for TCRα/δ associated DNA cleavage, but the molecular mechanism that leads to generation of the "oncogene partner" DNA break is unclear. Here we show that in ATM deficient primary mouse T cells, IgH/ TCRα/δ fusions arise at a remarkably similar frequency as in human AT lymphocytes. Recombinase-activating gene (RAG) is responsible for both TCRα/δ as well as IgH associated breaks on chromosome 12 (Chr12), which are subject to varying degrees of chromosomal degradation. We suggest a new model for how oncogenic translocations can arise from two non-concerted physiological DSBs.

AB - Translocations involving the T cell receptor alpha/delta (TCRα/δ) chain locus, which bring oncogenes in the proximity of the TCRα enhancer, are one of the hallmark features of human T cell malignancies from ataxia telangiectasia (AT) and non-AT patients. These lesions are frequently generated by the fusion of DNA breaks at the TCRα/δ locus to a disperse region centromeric of the immunoglobulin heavy chain (IgH) locus. Aberrant VDJ joining accounts for TCRα/δ associated DNA cleavage, but the molecular mechanism that leads to generation of the "oncogene partner" DNA break is unclear. Here we show that in ATM deficient primary mouse T cells, IgH/ TCRα/δ fusions arise at a remarkably similar frequency as in human AT lymphocytes. Recombinase-activating gene (RAG) is responsible for both TCRα/δ as well as IgH associated breaks on chromosome 12 (Chr12), which are subject to varying degrees of chromosomal degradation. We suggest a new model for how oncogenic translocations can arise from two non-concerted physiological DSBs.

KW - ATM

KW - T cell leukemia

KW - Translocations

KW - V(D)J recombination

UR - http://www.scopus.com/inward/record.url?scp=68449103871&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68449103871&partnerID=8YFLogxK

U2 - https://doi.org/10.4161/cc.8.15.9085

DO - https://doi.org/10.4161/cc.8.15.9085

M3 - Article

C2 - 19556863

SN - 1538-4101

VL - 8

SP - 2408

EP - 2412

JO - Cell Cycle

JF - Cell Cycle

IS - 15

ER -