Fragile sites limited to lymphocytes: Molecular recombination and malignancy

Hecht, Frederick; Hecht, Barbara K.; Kirsch, Ilan R.

doi:10.1016/0165-4608(87)90137-3

Cited by 31 publications

(17 citation statements)

References 27 publications

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“…These interlocus V(D)J recombinations create gross cytogenetic abnormalities, the breakpoints of which coincide with locations of the immunoglobulin and TCR genes. Such abnormalities have been described in normal PBL (8)(9)(10) and are increased in the PBL from agriculture workers exposed to pesticides (21) as well as in the PBL from AT patients (31,32 (18) but is only increased 5-to 10-fold in agriculture workers (22)(23)(24)(25)(26). This relationship is consistent with the continuous defect seen in AT patients and the transient defect seen in agriculture workers.…”

Section: Discussionsupporting

confidence: 76%

“…In addition to the aberrations found in malignant lymphocytes, the V(D)J recombinase can also generate cytogenetic abnormalities seen in peripheral blood lymphocytes (PBL) from normal individuals (8)(9)(10). These abnormalities are due to V(D)J recombination between two antigen-receptor loci, and they result in potentially functional hybrid antigen-receptor genes (11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

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Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies.

Lipkowitz

Garry

Kirsch

1992

Proc. Natl. Acad. Sci. U.S.A.

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V(D)J [variable-(diversity)-joining] re-arrangements occur between, as well as within, immune receptor loci, resulting in the generation of hybrid antigenreceptor genes and the formation of a variety of lymphocytespecific chromosomal aberrations. Such hybrid genes occur at a low frequency in the peripheral blood lymphocytes (PBL) of normal individuals but show a markedly increased incidence in the PBL of individuals with the autosomal recessive disease ataxia-telangiectasia. In this manuscript we demonstrate that the frequency of hybrid antigen-receptor genes is 10-to 20-fold increased in the PBL of an occupational group, agriculture workers, with related environmental exposures. Both ataxiatelangiectasia patients and this population of agriculture workers are at increased risk for lymphoid malignancy. This result suggests that the measurement of hybrid antigen receptorgenes in PBL may be a sensitive assay for a type of lymphocytespecific genomic instability. As a corollary, this assay may identify populations at risk of developing common types of lymphoid malignancy.In malignant lymphocytes there are data to suggest that the V(D)J [variable-(diversity)-joining] recombinase, which normally catalyzes recombination of DNA segments within each immunoglobulin and T-cell-receptor locus (1, 2), can play a central role as well in the generation of genetic changes that dysregulate certain growth-affecting genes, such as c-MYC, BCL-2, or SCL (2-7). In addition to the aberrations found in malignant lymphocytes, the V(D)J recombinase can also generate cytogenetic abnormalities seen in peripheral blood lymphocytes (PBL) from normal individuals (8-10). These abnormalities are due to V(D)J recombination between two antigen-receptor loci, and they result in potentially functional hybrid antigen-receptor genes (11-17). In patients with the inherited disease ataxia-telangiectasia (AT), a genomic instability syndrome associated with a high frequency of lymphoid malignancies (18), we have previously shown that the hybrid antigen-receptor gene formed by interlocus recombination between T-cell receptor y (TCRy) V segments and T-cell receptor 1 (TCRf3) J segments occurs in PBL at a frequency 50-to 100-fold higher than normal (17). This frequency is roughly the same as the increase in the risk for lymphoid malignancy of these individuals, so the frequency of hybrid antigen-receptor genes in the PBL of AT patients parallels their predisposition to lymphoid malignancy. There is also an increase in the frequency of the lymphocyte-specific cytogenetic abnormalities thought to be due to interlocus recombination in non-AT patients with non-Hodgkin lymphoma (19,20), further suggesting a relationship between these "innocent" translocations and lymphoid malignancies.Agriculture workers occupationally exposed to pesticides used in the production and storage of grain (such as phosphine, malathion, dichlorophenoxyacetic acid, chloropicrin, and captan) have a high frequency of cytogenetic abnormalities in their PBL (21), and we observed t...

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Section: Discussionsupporting

confidence: 76%

mentioning

confidence: 99%

Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies.

Lipkowitz

Garry

Kirsch

1992

Proc. Natl. Acad. Sci. U.S.A.

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“…Beside the hereditary factor, external events such as exposure to hazardous chemicals or ionizing radiation may induce genomic instability (47,48), which is correlated with the frequency of transrearrangements. The frequency of V␥-J␤ trans-rearrangements was 1:30,000 in PBL, and in parallel to this, the inversion in chromosome 7 was ϳ1:10,000 in T cells (49,50). Furthermore, in mice, the ratio of cis-to trans-rearrangements is 500-1000:1 in normal cells (45).…”

Section: The Trans-rearrangement As a Potential Biomarker For The Prementioning

confidence: 96%

TCR trans-Rearrangements: Biological Significance in Antigen Recognition vs the Role as Lymphoma Biomarker

Allam

Kabelitz

2006

The Journal of Immunology

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V(D)J rearrangements occur within loci of TCR and BCR genes, thus generating the diversity of the AgR repertoire. In addition, interlocus V(D)J rearrangements occur, giving rise to so-called “trans-rearrangements.” Such trans-rearrangements increase the diversity of the immune receptor repertoire and can be expressed as functional chimeric TCR proteins on the surface of T cells. Although chimeric receptors are not pathogenic per se, the frequency of AgR trans-rearrangements correlates with the level of genetic instability and thus could be used as a predictive biomarker for lymphoma risk.

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“…4) appears to be associated with development of T-CLL and T-PLL in AT and non-AT patients. Nonetheless, cytogenetic analysis of normal human B and T cells has shown the inv (14) chromosome to be present at a frequency ofabout 0.15% (25). With this observation in mind, single, cloned examples of an inv(14) B-cell tumor (26) and inv (14) T-cell tumor (6,7,20) with 14q32 breakpoints within the IGH locus at 14q32.3 (Fig.…”

mentioning

confidence: 99%

Analysis of a T-cell tumor-specific breakpoint cluster at human chromosome 14q32.

Mengle-Gaw

Albertson

Sherrington

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Cytogenetic abnormalities involving chromosome 14 band q32 are consistently observed in human T-cell tumors. Patients with ataxia-telangiectasia (AT) are especially prone to development of these tumors, which frequently carry either inversion inv(14)(qll;q32) or translocation t(14;14) (qll;q32) chromosomes. We have previously shown that the cytogenetic breakpoints of one t(14;14)(qll;q32) chromosome and two inv(14)(qll;q32) chromosomes in T-cell tumors from AT and non-AT patients join the T-cell receptor a chain locus, at chromosome band 14qll, with a region(s) at 14q32 centromeric of the immunoglobulin heavy chain variable region (VH) gene IGHV. We now show that these two inv(14) breakpoints are linked by 2

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Fragile sites limited to lymphocytes: Molecular recombination and malignancy

Cited by 31 publications

References 27 publications

Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies.

Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies.

TCR trans-Rearrangements: Biological Significance in Antigen Recognition vs the Role as Lymphoma Biomarker

Analysis of a T-cell tumor-specific breakpoint cluster at human chromosome 14q32.

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