Hybrid T cell receptor genes formed by interlocus recombination in normal and ataxia-telangiectasis lymphocytes

doi:10.1084/jem.172.2.409

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Hybrid T cell receptor genes formed by interlocus recombination in normal and ataxia-telangiectasis lymphocytes

S Lipkowitz, MH Stern and IR Kirsch
Navy Medical Oncology Branch, Naval Hospital, National Cancer Institute, Bethesda, Maryland.

In this paper, using polymerase chain reaction (PCR), we demonstrated the occurrence of hybrid genes formed by interlocus recombination between T cell receptor gamma (TCR-gamma) variable (V) regions and TCR- beta joining (J) regions in the peripheral blood lymphocytes (PBL) from normal individuals and patients with ataxia-telangiectasia (AT). Sequence analysis of the PCR-derived hybrid genes confirmed that site- specific V gamma-J beta recombination had occurred and showed that 10 of 23 genomic hybrid genes maintained a correct open reading frame. By dilution analysis, the frequency of these hybrid genes was 8 +/- 1/10(5) cells in normal PBL and 587 +/- 195/10(5) cells in AT PBL. These frequencies and the approximately 70-fold difference between the normal and AT samples are consistent with previous cytogenetic data examining the occurrence of an inversion of chromosome 7 in normal and AT PBL. We also demonstrated expression of these hybrid genes by PCR analysis of first-strand cDNA prepared from both normal and AT PBL. Sequence analysis of the PCR-amplified transcripts showed that, in contrast to the genomic hybrid genes, 19 of 22 expressed genes maintained a correct open reading frame at the V-J junction and correctly spliced the hybrid V-J exon to a TCR-beta constant region, thus allowing translation into a potentially functional hybrid TCR protein. Another type of hybrid TCR transcript was found in a which a rearranged TCR-gamma V-J exon was correctly spliced to a TCR-beta constant region. This form of hybrid gene may be formed by trans- splicing. These hybrid TCR genes may serve to increase the repertoire of the immune response. In addition, studies of their mechanism of formation and its misregulation in AT may provide insight into the nature of the chromosomal instability syndrome associated with AT. The mechanism underlying hybrid gene formation may be analogous to the mechanism underlying rearrangements between putative growth-affecting genes and the antigen receptor loci, which are associated with AT lymphocyte clones and lymphoid malignancies.
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Lew, S., Franco, D., Chang, Y. (2000). Activation of V(D)J Recombination Induces the Formation of Interlocus Joints and Hybrid Joints in scid Pre-B-Cell Lines. Mol. Cell. Biol. 20: 7170-7177 [Abstract] [Full Text]
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Vanasse, G. J., Concannon, P., Willerford, D. M. (1999). Regulated Genomic Instability and Neoplasia in the Lymphoid Lineage. Blood 94: 3997-4010 [Full Text]
Fukao, T., Kaneko, H., Birrell, G., Gatei, M., Tashita, H., Yoshida, T., Cross, S., Kedar, P., Watters, D., Khana, K. K., Misko, I., Kondo, N., Lavin, M. F. (1999). ATM Is Upregulated During the Mitogenic Response in Peripheral Blood Mononuclear Cells. Blood 94: 1998-2006 [Abstract] [Full Text]
Retiere, C., Halary, F., Peyrat, M.-A., Le Deist, F., Bonneville, M., Hallet, M.-M. (1999). The Mechanism of Chromosome 7 Inversion in Human Lymphocytes Expressing Chimeric {gamma}{beta} TCR. J. Immunol. 162: 903-910 [Abstract] [Full Text]
HUYE, L.E., HAN, J.-O., ROTH, D.B. (1999). What Prevents Intermolecular V(D)J Recombination?. Cold Spring Harb Symp Quant Biol 64: 191-196 [Abstract]
Green, E., McConville, C. M., Powell, J. E., Mann, J. R., Darbyshire, P. J., Taylor, A. M. R., Stankovic, T. (1998). Clonal Diversity of Ig and T-Cell-Receptor Gene Rearrangements Identifies a Subset of Childhood B-Precursor Acute Lymphoblastic Leukemia With Increased Risk of Relapse. Blood 92: 952-958 [Abstract] [Full Text]
Kirsch, I.R., Abdallah, J.M., Bertness, V.L., Hale, M., Lipkowitz, S., Lista, F., Lombardi, D.P. (1994). Lymphocyte-specific Genetic Instability and Cancer. Cold Spring Harb Symp Quant Biol 59: 287-295 [Abstract]
Meyn, M. (1993). High spontaneous intrachromosomal recombination rates in ataxia-telangiectasia. Science 260: 1327-1330 [Abstract]
Lin, W., Desiderio, S (1993). Regulation of V(D)J recombination activator protein RAG-2 by phosphorylation. Science 260: 953-959 [Abstract]
Aplan, P., Lombardi, D., Ginsberg, A., Cossman, J, Bertness, V., Kirsch, I. (1990). Disruption of the human SCL locus by "illegitimate" V-(D)-J recombinase activity. Science 250: 1426-1429 [Abstract]