{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T10:22:23Z","timestamp":1792059743855,"version":"4.4.0"},"reference-count":47,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1,7]]},"abstract":"<jats:p>Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)\/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin\u2019s lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.<\/jats:p>","DOI":"10.1084\/jem.20011578","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:48:33Z","timestamp":1027702113000},"page":"85-98","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":132,"title":["V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites"],"prefix":"10.1084","volume":"195","author":[{"given":"Rodrig","family":"Marculescu","sequence":"first","affiliation":[{"name":"1Department of Internal Medicine I, Division of Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trang","family":"Le","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Division of Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Simon","sequence":"additional","affiliation":[{"name":"2Department of Surgery, University of Vienna, A-1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Jaeger","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Division of Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Nadel","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Division of Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2002,1,7]]},"reference":[{"key":"2023072511213197900_b1-1950085","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1006\/smim.1994.1020","article-title":"The mechanism of V(D)J recombination: site-specificity, reaction fidelity and immunologic diversity","volume":"6","author":"Lieber","year":"1994","journal-title":"Semin. Immunol"},{"key":"2023072511213197900_b2-1950085","doi-asserted-by":"crossref","first-page":"3125","DOI":"10.1128\/MCB.17.6.3125","article-title":"Cryptic signals and the fidelity of V(D)J joining","volume":"17","author":"Lewis","year":"1997","journal-title":"Mol. Cell. Biol"},{"key":"2023072511213197900_b3-1950085","first-page":"1","article-title":"Chromosomal translocations in lymphoid neoplasia: a reappraisal of the recombinase model","volume":"2","author":"Tycko","year":"1990","journal-title":"Cancer Cells"},{"key":"2023072511213197900_b4-1950085","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/S0002-9440(10)65716-1","article-title":"Warner-Lambert\/Parke-Davis Award Lecture. Pathological and physiological double-strand breaks: roles in cancer, aging, and the immune system","volume":"153","author":"Lieber","year":"1998","journal-title":"Am. J. Pathol"},{"key":"2023072511213197900_b5-1950085","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1006\/smim.1994.1021","article-title":"Influence of the V(D)J recombination mechanism on the formation of the primary T and B cell repertoires","volume":"6","author":"Feeney","year":"1994","journal-title":"Semin. Immunol"},{"key":"2023072511213197900_b6-1950085","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1126\/science.3120312","article-title":"Two pairs of recombination signals are sufficient to cause immunoglobulin V-(D)-J joining","volume":"238","author":"Akira","year":"1987","journal-title":"Science"},{"key":"2023072511213197900_b7-1950085","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1101\/gad.3.7.1053","article-title":"V(D)J recombination: a functional definition of the joining signals","volume":"3","author":"Hesse","year":"1989","journal-title":"Genes Dev"},{"key":"2023072511213197900_b8-1950085","doi-asserted-by":"crossref","first-page":"4520","DOI":"10.4049\/jimmunol.153.10.4520","article-title":"Essential residues in V(D)J recombination signals","volume":"153","author":"Akamatsu","year":"1994","journal-title":"J. Immunol"},{"key":"2023072511213197900_b9-1950085","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1007\/BF02660064","article-title":"Mouse RSS spacer sequences affect the rate of V(D)J recombination","volume":"44","author":"Fanning","year":"1996","journal-title":"Immunogenetics"},{"key":"2023072511213197900_b10-1950085","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1084\/jem.187.9.1495","article-title":"Sequence of the spacer in the recombination signal sequence affects V(D)J rearrangement frequency and correlates with nonrandom Vkappa usage in vivo","volume":"187","author":"Nadel","year":"1998","journal-title":"J. Exp. Med"},{"key":"2023072511213197900_b11-1950085","doi-asserted-by":"crossref","first-page":"6068","DOI":"10.4049\/jimmunol.161.11.6068","article-title":"Decreased frequency of rearrangement due to the synergistic effect of nucleotide changes in the heptamer and nonamer of the recombination signal sequence of the V kappa gene A2b, which is associated with increased susceptibility of Navajos to Haemophilus influenzae type b disease","volume":"161","author":"Nadel","year":"1998","journal-title":"J. Immunol"},{"key":"2023072511213197900_b12-1950085","doi-asserted-by":"crossref","first-page":"29126","DOI":"10.1074\/jbc.M103797200","article-title":"Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints","volume":"276","author":"Raghavan","year":"2001","journal-title":"J. Biol. Chem"},{"key":"2023072511213197900_b13-1950085","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1126\/science.3929382","article-title":"The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining","volume":"229","author":"Tsujimoto","year":"1985","journal-title":"Science"},{"key":"2023072511213197900_b14-1950085","doi-asserted-by":"crossref","first-page":"7439","DOI":"10.1073\/pnas.82.21.7439","article-title":"Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18","volume":"82","author":"Cleary","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023072511213197900_b15-1950085","doi-asserted-by":"crossref","first-page":"2396","DOI":"10.1073\/pnas.84.8.2396","article-title":"Mechanism of the t(14;18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners","volume":"84","author":"Bakhshi","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023072511213197900_b16-1950085","first-page":"347","article-title":"The reciprocal partners of both the t(14; 18) and the t(11; 14) translocations involved in B-cell neoplasms are rearranged by the same mechanism","volume":"2","author":"Tsujimoto","year":"1988","journal-title":"Oncogene"},{"key":"2023072511213197900_b17-1950085","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1084\/jem.169.2.369","article-title":"Consistent breakage between consensus recombinase heptamers of chromosome 9 DNA in a recurrent chromosomal translocation of human T cell leukemia","volume":"169","author":"Tycko","year":"1989","journal-title":"J. Exp. Med"},{"key":"2023072511213197900_b18-1950085","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1182\/blood.V73.6.1672.1672","article-title":"The T-cell receptor delta chain locus is disrupted in the T-ALL associated t(11;14)(p13;q11) translocation","volume":"73","author":"Champagne","year":"1989","journal-title":"Blood"},{"key":"2023072511213197900_b19-1950085","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1084\/jem.171.2.489","article-title":"The chromosome translocation (11;14)(p13;q11) associated with T cell acute leukemia. Asymmetric diversification of the translocational junctions","volume":"171","author":"Cheng","year":"1990","journal-title":"J. Exp. Med"},{"key":"2023072511213197900_b20-1950085","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1002\/j.1460-2075.1988.tb03040.x","article-title":"A cluster of chromosome 11p13 translocations found via distinct D-D and D-D-J rearrangements of the human T cell receptor delta chain gene","volume":"7","author":"Boehm","year":"1988","journal-title":"EMBO J"},{"key":"2023072511213197900_b21-1950085","first-page":"577","article-title":"A study of chromosome 11p13 translocations involving TCR beta and TCR delta in human T cell leukaemia","volume":"6","author":"Garcia","year":"1991","journal-title":"Oncogene"},{"key":"2023072511213197900_b22-1950085","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/j.1460-2075.1990.tb08126.x","article-title":"The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein","volume":"9","author":"Chen","year":"1990","journal-title":"EMBO J"},{"key":"2023072511213197900_b23-1950085","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1084\/jem.172.5.1403","article-title":"Coding sequences of the tal-1 gene are disrupted by chromosome translocation in human T cell leukemia","volume":"172","author":"Chen","year":"1990","journal-title":"J. Exp. Med"},{"key":"2023072511213197900_b24-1950085","doi-asserted-by":"crossref","first-page":"10128","DOI":"10.1073\/pnas.86.24.10128","article-title":"The gene SCL is expressed during early hematopoiesis and encodes a differentiation-related DNA-binding motif","volume":"86","author":"Begley","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023072511213197900_b25-1950085","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.1073\/pnas.86.13.5039","article-title":"Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma","volume":"86","author":"Finger","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023072511213197900_b26-1950085","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/0952-7915(95)80074-3","article-title":"The role of chromosome translocations in T cell acute leukemia","volume":"7","author":"Hwang","year":"1995","journal-title":"Curr. Opin. Immunol"},{"key":"2023072511213197900_b27-1950085","doi-asserted-by":"crossref","first-page":"3768","DOI":"10.1128\/MCB.17.7.3768","article-title":"Nucleotide deletion and P addition in V(D)J recombination: a determinant role of the coding-end sequence","volume":"17","author":"Nadel","year":"1997","journal-title":"Mol. Cell. Biol"},{"key":"2023072511213197900_b28-1950085","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.1182\/blood.V95.11.3520","article-title":"Follicular lymphomas\u2019 BCL-2\/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation","volume":"95","author":"Jaeger","year":"2000","journal-title":"Blood"},{"key":"2023072511213197900_b29-1950085","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/carcin\/17.5.1013","article-title":"Quantification of t(14;18) in the lymphocytes of healthy adult humans as a possible biomarker for environmental exposures to carcinogens","volume":"17","author":"Fuscoe","year":"1996","journal-title":"Carcinogenesis"},{"key":"2023072511213197900_b30-1950085","first-page":"1437","article-title":"Chromosome t(11;14)(q13;q32) breakpoints in centrocytic lymphoma are highly localized at the bcl-1 major translocation cluster","volume":"7","author":"Williams","year":"1993","journal-title":"Leukemia"},{"key":"2023072511213197900_b31-1950085","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/S0167-5699(00)01650-9","article-title":"Molecular insights into the immunopathogenesis of follicular lymphoma","volume":"21","author":"Stamatopoulos","year":"2000","journal-title":"Immunol. Today"},{"key":"2023072511213197900_b32-1950085","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1111\/j.1365-2141.1999.01314.x","article-title":"Molecular analysis of bcl-1\/IgH junctional sequences in mantle cell lymphoma: potential mechanism of the t(11;14) chromosomal translocation","volume":"105","author":"Stamatopoulos","year":"1999","journal-title":"Br. J. Haematol"},{"key":"2023072511213197900_b33-1950085","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1182\/blood.V96.5.1947","article-title":"V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma","volume":"96","author":"Vaandrager","year":"2000","journal-title":"Blood"},{"key":"2023072511213197900_b34-1950085","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1126\/science.2551037","article-title":"T cell receptor gene trans-rearrangements: chimeric gamma-delta genes in normal lymphoid tissues","volume":"245","author":"Tycko","year":"1989","journal-title":"Science"},{"key":"2023072511213197900_b35-1950085","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1128\/MCB.17.2.887","article-title":"Assessing the pathogenic potential of the V(D)J recombinase by interlocus immunoglobulin light-chain gene rearrangement","volume":"17","author":"Bailey","year":"1997","journal-title":"Mol. Cell. Biol"},{"key":"2023072511213197900_b36-1950085","doi-asserted-by":"crossref","DOI":"10.3109\/10428190109097743","article-title":"Novel insights into the mechanism of t(14;18)(q32;q21) translocation in follicular lymphoma","volume-title":"Leuk. Lymphoma","author":"Nadel","year":"2001"},{"key":"2023072511213197900_b37-1950085","first-page":"1629","article-title":"Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma","volume":"61","author":"Welzel","year":"2001","journal-title":"Cancer Res"},{"key":"2023072511213197900_b38-1950085","doi-asserted-by":"crossref","first-page":"3228","DOI":"10.4049\/jimmunol.140.9.3228","article-title":"Rearrangement of IgH genes in normal thymocyte development","volume":"140","author":"Born","year":"1988","journal-title":"J. Immunol"},{"key":"2023072511213197900_b39-1950085","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/j.1460-2075.1990.tb08087.x","article-title":"Separate elements control DJ and VDJ rearrangement in a transgenic recombination substrate","volume":"9","author":"Ferrier","year":"1990","journal-title":"EMBO J"},{"key":"2023072511213197900_b40-1950085","doi-asserted-by":"crossref","first-page":"7871","DOI":"10.1073\/pnas.93.15.7871","article-title":"Gene-targeted deletion and replacement mutations of the T-cell receptor beta-chain enhancer: the role of enhancer elements in controlling V(D)J recombination accessibility","volume":"93","author":"Bories","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023072511213197900_b41-1950085","doi-asserted-by":"crossref","first-page":"5032","DOI":"10.1128\/MCB.20.14.5032-5040.2000","article-title":"Postcleavage sequence specificity in V(D)J recombination","volume":"20","author":"Agard","year":"2000","journal-title":"Mol. Cell. Biol"},{"key":"2023072511213197900_b42-1950085","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0065-2776(08)60610-0","article-title":"Accessibility control of V(D)J recombination: lessons from gene targeting","volume":"69","author":"Hempel","year":"1998","journal-title":"Adv. Immunol"},{"key":"2023072511213197900_b43-1950085","first-page":"253","article-title":"Molecular genetics of lymphogenesis: an overview","volume-title":"The Non-Hodgkin\u2019s Lymphomas","author":"Kirsch","year":"1997","edition":"Second Edition"},{"key":"2023072511213197900_b44-1950085","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1084\/jem.175.6.1575","article-title":"BCL2 oncogene translocation is mediated by a chi-like consensus","volume":"175","author":"Wyatt","year":"1992","journal-title":"J. Exp. Med"},{"key":"2023072511213197900_b45-1950085","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1182\/blood.V81.7.1833.1833","article-title":"Mechanism of the chromosomal translocation t(14;18) in lymphoma: detection of a 45-Kd breakpoint binding protein","volume":"81","author":"Jaeger","year":"1993","journal-title":"Blood"},{"key":"2023072511213197900_b46-1950085","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S0092-8674(00)81587-1","article-title":"DNA transposition by the RAG1 and RAG2 proteins: a possible source of oncogenic translocations","volume":"94","author":"Hiom","year":"1998","journal-title":"Cell"},{"key":"2023072511213197900_b47-1950085","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/29457","article-title":"Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system","volume":"394","author":"Agrawal","year":"1998","journal-title":"Nature"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/195\/1\/85\/1704791\/jem195185.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/195\/1\/85\/1704791\/jem195185.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T11:22:09Z","timestamp":1690284129000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/195\/1\/85\/8267\/V-D-J-mediated-Translocations-in-Lymphoid"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,1,7]]},"references-count":47,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2002,1,7]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20011578","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,1,7]]}}}