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. 1993 Apr 1;177(4):965–977. doi: 10.1084/jem.177.4.965

Site-specific deletions involving the tal-1 and sil genes are restricted to cells of the T cell receptor alpha/beta lineage: T cell receptor delta gene deletion mechanism affects multiple genes

PMCID: PMC2190963  PMID: 8459224

Abstract

Site-specific deletions in the tal-1 gene are reported to occur in 12- 26% of T cell acute lymphoblastic leukemias (T-ALL). So far two main types of tal-1 deletions have been described. Upon analysis of 134 T- ALL we have found two new types of tal-1 deletions. These four types of deletions juxtapose the 5' part of the tal-1 gene to the sil gene promoter, thereby deleting all coding sil exons but leaving the coding tal-1 exons undamaged. The recombination signal sequences (RSS) and fusion regions of the tal-1 deletion breakpoints strongly resemble the RSS and junctional regions of immunoglobulin/T cell receptor (TCR) gene rearrangements, which implies that they are probably caused by the same V(D)J recombinase complex. Analysis of the 134 T-ALL suggested that the occurrence of tal-1 deletions is associated with the CD3 phenotype, because no tal-1 deletions were found in 25 TCR-gamma/delta + T-ALL, whereas 8 of the 69 CD3- T-ALL and 11 of the 40 TCR-alpha/beta + T-ALL contained such a deletion. Careful examination of all TCR genes revealed that tal-1 deletions exclusively occurred in CD3- or CD3+ T- ALL of the alpha/beta lineage with a frequency of 18% in T-ALL with one deleted TCR-delta allele, and a frequency of 34% in T-ALL with TCR- delta gene deletions on both alleles. Therefore, we conclude that alpha/beta lineage commitment of the T-ALL and especially the extent of TCR-delta gene deletions determines the chance of a tal-1 deletion. This suggests that tal-1 deletions are mediated via the same deletion mechanism as TCR-delta gene deletions.

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Selected References

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  1. Akira S., Okazaki K., Sakano H. Two pairs of recombination signals are sufficient to cause immunoglobulin V-(D)-J joining. Science. 1987 Nov 20;238(4830):1134–1138. doi: 10.1126/science.3120312. [DOI] [PubMed] [Google Scholar]
  2. Alt F. W., Baltimore D. Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions. Proc Natl Acad Sci U S A. 1982 Jul;79(13):4118–4122. doi: 10.1073/pnas.79.13.4118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aplan P. D., Begley C. G., Bertness V., Nussmeier M., Ezquerra A., Coligan J., Kirsch I. R. The SCL gene is formed from a transcriptionally complex locus. Mol Cell Biol. 1990 Dec;10(12):6426–6435. doi: 10.1128/mcb.10.12.6426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aplan P. D., Lombardi D. P., Ginsberg A. M., Cossman J., Bertness V. L., Kirsch I. R. Disruption of the human SCL locus by "illegitimate" V-(D)-J recombinase activity. Science. 1990 Dec 7;250(4986):1426–1429. doi: 10.1126/science.2255914. [DOI] [PubMed] [Google Scholar]
  5. Aplan P. D., Lombardi D. P., Kirsch I. R. Structural characterization of SIL, a gene frequently disrupted in T-cell acute lymphoblastic leukemia. Mol Cell Biol. 1991 Nov;11(11):5462–5469. doi: 10.1128/mcb.11.11.5462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Aplan P. D., Lombardi D. P., Reaman G. H., Sather H. N., Hammond G. D., Kirsch I. R. Involvement of the putative hematopoietic transcription factor SCL in T-cell acute lymphoblastic leukemia. Blood. 1992 Mar 1;79(5):1327–1333. [PubMed] [Google Scholar]
  7. Baer R., Boehm T., Yssel H., Spits H., Rabbitts T. H. Complex rearrangements within the human J delta-C delta/J alpha-C alpha locus and aberrant recombination between J alpha segments. EMBO J. 1988 Jun;7(6):1661–1668. doi: 10.1002/j.1460-2075.1988.tb02993.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Begley C. G., Aplan P. D., Davey M. P., Nakahara K., Tchorz K., Kurtzberg J., Hershfield M. S., Haynes B. F., Cohen D. I., Waldmann T. A. Chromosomal translocation in a human leukemic stem-cell line disrupts the T-cell antigen receptor delta-chain diversity region and results in a previously unreported fusion transcript. Proc Natl Acad Sci U S A. 1989 Mar;86(6):2031–2035. doi: 10.1073/pnas.86.6.2031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Begley C. G., Aplan P. D., Denning S. M., Haynes B. F., Waldmann T. A., Kirsch I. R. The gene SCL is expressed during early hematopoiesis and encodes a differentiation-related DNA-binding motif. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10128–10132. doi: 10.1073/pnas.86.24.10128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bernard O., Guglielmi P., Jonveaux P., Cherif D., Gisselbrecht S., Mauchauffe M., Berger R., Larsen C. J., Mathieu-Mahul D. Two distinct mechanisms for the SCL gene activation in the t(1;14) translocation of T-cell leukemias. Genes Chromosomes Cancer. 1990 Jan;1(3):194–208. doi: 10.1002/gcc.2870010303. [DOI] [PubMed] [Google Scholar]
  11. Bernard O., Lecointe N., Jonveaux P., Souyri M., Mauchauffé M., Berger R., Larsen C. J., Mathieu-Mahul D. Two site-specific deletions and t(1;14) translocation restricted to human T-cell acute leukemias disrupt the 5' part of the tal-1 gene. Oncogene. 1991 Aug;6(8):1477–1488. [PubMed] [Google Scholar]
  12. Blackwell T. K., Alt F. W. Molecular characterization of the lymphoid V(D)J recombination activity. J Biol Chem. 1989 Jun 25;264(18):10327–10330. [PubMed] [Google Scholar]
  13. Boehm T., Baer R., Lavenir I., Forster A., Waters J. J., Nacheva E., Rabbitts T. H. The mechanism of chromosomal translocation t(11;14) involving the T-cell receptor C delta locus on human chromosome 14q11 and a transcribed region of chromosome 11p15. EMBO J. 1988 Feb;7(2):385–394. doi: 10.1002/j.1460-2075.1988.tb02825.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Boehm T., Rabbitts T. H. A chromosomal basis of lymphoid malignancy in man. Eur J Biochem. 1989 Oct 20;185(1):1–17. doi: 10.1111/j.1432-1033.1989.tb15074.x. [DOI] [PubMed] [Google Scholar]
  15. Breit T. M., Wolvers-Tettero I. L., Hählen K., van Wering E. R., van Dongen J. J. Extensive junctional diversity of gamma delta T-cell receptors expressed by T-cell acute lymphoblastic leukemias: implications for the detection of minimal residual disease. Leukemia. 1991 Dec;5(12):1076–1086. [PubMed] [Google Scholar]
  16. Breit T. M., Wolvers-Tettero I. L., van Dongen J. J. Receptor diversity of human T-cell receptor gamma delta expressing cells. Prog Histochem Cytochem. 1992;26(1-4):182–193. doi: 10.1016/s0079-6336(11)80094-x. [DOI] [PubMed] [Google Scholar]
  17. Brown L., Cheng J. T., Chen Q., Siciliano M. J., Crist W., Buchanan G., Baer R. Site-specific recombination of the tal-1 gene is a common occurrence in human T cell leukemia. EMBO J. 1990 Oct;9(10):3343–3351. doi: 10.1002/j.1460-2075.1990.tb07535.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Carroll A. J., Crist W. M., Link M. P., Amylon M. D., Pullen D. J., Ragab A. H., Buchanan G. R., Wimmer R. S., Vietti T. J. The t(1;14)(p34;q11) is nonrandom and restricted to T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1990 Sep 15;76(6):1220–1224. [PubMed] [Google Scholar]
  19. Chen Q., Cheng J. T., Tasi L. H., Schneider N., Buchanan G., Carroll A., Crist W., Ozanne B., Siciliano M. J., Baer R. The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein. EMBO J. 1990 Feb;9(2):415–424. doi: 10.1002/j.1460-2075.1990.tb08126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Chen Q., Yang C. Y., Tsan J. T., Xia Y., Ragab A. H., Peiper S. C., Carroll A., Baer R. Coding sequences of the tal-1 gene are disrupted by chromosome translocation in human T cell leukemia. J Exp Med. 1990 Nov 1;172(5):1403–1408. doi: 10.1084/jem.172.5.1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. De Klein A., Hagemeijer A., Bartram C. R., Houwen R., Hoefsloot L., Carbonell F., Chan L., Barnett M., Greaves M., Kleihauer E. bcr rearrangement and translocation of the c-abl oncogene in Philadelphia positive acute lymphoblastic leukemia. Blood. 1986 Dec;68(6):1369–1375. [PubMed] [Google Scholar]
  22. Duby A. D., Klein K. A., Murre C., Seidman J. G. A novel mechanism of somatic rearrangement predicted by a human T-cell antigen receptor beta-chain complementary DNA. Science. 1985 Jun 7;228(4704):1204–1206. doi: 10.1126/science.3839095. [DOI] [PubMed] [Google Scholar]
  23. Finger L. R., Harvey R. C., Moore R. C., Showe L. C., Croce C. M. A common mechanism of chromosomal translocation in T- and B-cell neoplasia. Science. 1986 Nov 21;234(4779):982–985. doi: 10.1126/science.3490692. [DOI] [PubMed] [Google Scholar]
  24. Finger L. R., Kagan J., Christopher G., Kurtzberg J., Hershfield M. S., Nowell P. C., Croce C. M. Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5039–5043. doi: 10.1073/pnas.86.13.5039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Fuscoe J. C., Zimmerman L. J., Lippert M. J., Nicklas J. A., O'Neill J. P., Albertini R. J. V(D)J recombinase-like activity mediates hprt gene deletion in human fetal T-lymphocytes. Cancer Res. 1991 Nov 1;51(21):6001–6005. [PubMed] [Google Scholar]
  26. Green A. R., Lints T., Visvader J., Harvey R., Begley C. G. SCL is coexpressed with GATA-1 in hemopoietic cells but is also expressed in developing brain. Oncogene. 1992 Apr;7(4):653–660. [PubMed] [Google Scholar]
  27. Green A. R., Salvaris E., Begley C. G. Erythroid expression of the 'helix-loop-helix' gene, SCL. Oncogene. 1991 Mar;6(3):475–479. [PubMed] [Google Scholar]
  28. Hesse J. E., Lieber M. R., Mizuuchi K., Gellert M. V(D)J recombination: a functional definition of the joining signals. Genes Dev. 1989 Jul;3(7):1053–1061. doi: 10.1101/gad.3.7.1053. [DOI] [PubMed] [Google Scholar]
  29. Hockett R. D., de Villartay J. P., Pollock K., Poplack D. G., Cohen D. I., Korsmeyer S. J. Human T-cell antigen receptor (TCR) delta-chain locus and elements responsible for its deletion are within the TCR alpha-chain locus. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9694–9698. doi: 10.1073/pnas.85.24.9694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hsu H. L., Cheng J. T., Chen Q., Baer R. Enhancer-binding activity of the tal-1 oncoprotein in association with the E47/E12 helix-loop-helix proteins. Mol Cell Biol. 1991 Jun;11(6):3037–3042. doi: 10.1128/mcb.11.6.3037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lafaille J. J., DeCloux A., Bonneville M., Takagaki Y., Tonegawa S. Junctional sequences of T cell receptor gamma delta genes: implications for gamma delta T cell lineages and for a novel intermediate of V-(D)-J joining. Cell. 1989 Dec 1;59(5):859–870. doi: 10.1016/0092-8674(89)90609-0. [DOI] [PubMed] [Google Scholar]
  32. Loh E. Y., Cwirla S., Serafini A. T., Phillips J. H., Lanier L. L. Human T-cell-receptor delta chain: genomic organization, diversity, and expression in populations of cells. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9714–9718. doi: 10.1073/pnas.85.24.9714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Macintyre E. A., Smit L., Ritz J., Kirsch I. R., Strominger J. L. Disruption of the SCL locus in T-lymphoid malignancies correlates with commitment to the T-cell receptor alpha beta lineage. Blood. 1992 Sep 15;80(6):1511–1520. [PubMed] [Google Scholar]
  34. McGinniss M. J., Falta M. T., Sullivan L. M., Albertini R. J. In vivo hprt mutant frequencies in T-cells of normal human newborns. Mutat Res. 1990 Feb;240(2):117–126. doi: 10.1016/0165-1218(90)90015-t. [DOI] [PubMed] [Google Scholar]
  35. McGinniss M. J., Nicklas J. A., Albertini R. J. Molecular analyses of in vivo hprt mutations in human T-lymphocytes: IV. Studies in newborns. Environ Mol Mutagen. 1989;14(4):229–237. doi: 10.1002/em.2850140404. [DOI] [PubMed] [Google Scholar]
  36. Murre C., McCaw P. S., Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. doi: 10.1016/0092-8674(89)90682-x. [DOI] [PubMed] [Google Scholar]
  37. Murre C., McCaw P. S., Vaessin H., Caudy M., Jan L. Y., Jan Y. N., Cabrera C. V., Buskin J. N., Hauschka S. D., Lassar A. B. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell. 1989 Aug 11;58(3):537–544. doi: 10.1016/0092-8674(89)90434-0. [DOI] [PubMed] [Google Scholar]
  38. Quertermous T., Strauss W. M., Van Dongen J. J., Seidman J. G. Human T cell gamma chain joining regions and T cell development. J Immunol. 1987 Apr 15;138(8):2687–2690. [PubMed] [Google Scholar]
  39. Schatz D. G., Oettinger M. A., Schlissel M. S. V(D)J recombination: molecular biology and regulation. Annu Rev Immunol. 1992;10:359–383. doi: 10.1146/annurev.iy.10.040192.002043. [DOI] [PubMed] [Google Scholar]
  40. Visvader J., Begley C. G., Adams J. M. Differential expression of the LYL, SCL and E2A helix-loop-helix genes within the hemopoietic system. Oncogene. 1991 Feb;6(2):187–194. [PubMed] [Google Scholar]
  41. Visvader J., Begley C. G. Helix-loop-helix genes translocated in lymphoid leukemia. Trends Biochem Sci. 1991 Sep;16(9):330–333. doi: 10.1016/0968-0004(91)90137-k. [DOI] [PubMed] [Google Scholar]
  42. de Villartay J. P., Hockett R. D., Coran D., Korsmeyer S. J., Cohen D. I. Deletion of the human T-cell receptor delta-gene by a site-specific recombination. Nature. 1988 Sep 8;335(6186):170–174. doi: 10.1038/335170a0. [DOI] [PubMed] [Google Scholar]
  43. van Dongen J. J., Comans-Bitter W. M., Wolvers-Tettero I. L., Borst J. Development of human T lymphocytes and their thymus-dependency. Thymus. 1990 Nov-Dec;16(3-4):207–234. [PubMed] [Google Scholar]
  44. van Dongen J. J., Wolvers-Tettero I. L. Analysis of immunoglobulin and T cell receptor genes. Part I: Basic and technical aspects. Clin Chim Acta. 1991 Apr;198(1-2):1–91. doi: 10.1016/0009-8981(91)90246-9. [DOI] [PubMed] [Google Scholar]

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