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. 1988 Apr;81(4):989–996. doi: 10.1172/JCI113453

Comparison of T cell receptor alpha, beta, and gamma gene rearrangement and expression in T cell acute lymphoblastic leukemia.

J Hara 1, S H Benedict 1, E Champagne 1, T W Mak 1, M Minden 1, E W Gelfand 1
PMCID: PMC329622  PMID: 3162460

Abstract

We have analyzed the configuration of the T cell receptor (TCR) alpha gene using newly developed genomic joining region (J alpha) probes, which cover approximately 80 kb of the J alpha region upstream from the constant region in 19 patients with T cell acute lymphoblastic leukemia (T-ALL) and in three CD3- leukemic T cell lines (HSB2, CEM, and MOLT4). In parallel, transcription of the TCR-alpha, beta, and gamma genes was examined in 11 of these patients and in the T cell lines. All T-ALL and the three T cell lines exhibited both TCR-gamma and beta gene rearrangements. 8 of 10 T-ALL and all T cell lines expressed TCR-gamma transcripts. All samples tested expressed both TCR-beta and CD3-gamma transcripts. TCR alpha transcripts were only observed in CD3+ T-ALL but not in CD3- T-ALL or the CD3- cell lines. Among the CD3+ T-ALL, eight had TCR-alpha gene rearrangements. In addition, TCR-alpha gene rearrangements were detected in one CD3- T-ALL and all three T cell lines. These leukemic cells may represent a transient stage between rearrangement and expression and provide an opportunity for analyzing the mechanism regulating the expression of the TCR-alpha gene.

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Selected References

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  1. Acuto O., Fabbi M., Bensussan A., Milanese C., Campen T. J., Royer H. D., Reinherz E. L. The human T-cell receptor. J Clin Immunol. 1985 May;5(3):141–157. doi: 10.1007/BF00915505. [DOI] [PubMed] [Google Scholar]
  2. Bank I., DePinho R. A., Brenner M. B., Cassimeris J., Alt F. W., Chess L. A functional T3 molecule associated with a novel heterodimer on the surface of immature human thymocytes. Nature. 1986 Jul 10;322(6075):179–181. doi: 10.1038/322179a0. [DOI] [PubMed] [Google Scholar]
  3. Benedict S. H., Maki Y., Vogt P. K. Avian retrovirus S13: properties of the genome and of the transformation-specific protein. Virology. 1985 Aug;145(1):154–164. doi: 10.1016/0042-6822(85)90210-7. [DOI] [PubMed] [Google Scholar]
  4. Borst J., van de Griend R. J., van Oostveen J. W., Ang S. L., Melief C. J., Seidman J. G., Bolhuis R. L. A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes. Nature. 1987 Feb 19;325(6106):683–688. doi: 10.1038/325683a0. [DOI] [PubMed] [Google Scholar]
  5. Brenner M. B., McLean J., Dialynas D. P., Strominger J. L., Smith J. A., Owen F. L., Seidman J. G., Ip S., Rosen F., Krangel M. S. Identification of a putative second T-cell receptor. Nature. 1986 Jul 10;322(6075):145–149. doi: 10.1038/322145a0. [DOI] [PubMed] [Google Scholar]
  6. Brenner M. B., McLean J., Scheft H., Riberdy J., Ang S. L., Seidman J. G., Devlin P., Krangel M. S. Two forms of the T-cell receptor gamma protein found on peripheral blood cytotoxic T lymphocytes. Nature. 1987 Feb 19;325(6106):689–694. doi: 10.1038/325689a0. [DOI] [PubMed] [Google Scholar]
  7. Brenner M. B., Trowbridge I. S., Strominger J. L. Cross-linking of human T cell receptor proteins: association between the T cell idiotype beta subunit and the T3 glycoprotein heavy subunit. Cell. 1985 Jan;40(1):183–190. doi: 10.1016/0092-8674(85)90321-6. [DOI] [PubMed] [Google Scholar]
  8. Chien Y. H., Iwashima M., Kaplan K. B., Elliott J. F., Davis M. M. A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. 1987 Jun 25-Jul 1Nature. 327(6124):677–682. doi: 10.1038/327677a0. [DOI] [PubMed] [Google Scholar]
  9. Collins M. K., Tanigawa G., Kissonerghis A. M., Ritter M., Price K. M., Tonegawa S., Owen M. J. Regulation of T-cell receptor gene expression in human T-cell development. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4503–4507. doi: 10.1073/pnas.82.13.4503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Davey M. P., Bongiovanni K. F., Kaulfersch W., Quertermous T., Seidman J. G., Hershfield M. S., Kurtzberg J., Haynes B. F., Davis M. M., Waldmann T. A. Immunoglobulin and T-cell receptor gene rearrangement and expression in human lymphoid leukemia cells at different stages of maturation. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8759–8763. doi: 10.1073/pnas.83.22.8759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  12. Furley A. J., Mizutani S., Weilbaecher K., Dhaliwal H. S., Ford A. M., Chan L. C., Molgaard H. V., Toyonaga B., Mak T., van den Elsen P. Developmentally regulated rearrangement and expression of genes encoding the T cell receptor-T3 complex. Cell. 1986 Jul 4;46(1):75–87. doi: 10.1016/0092-8674(86)90861-5. [DOI] [PubMed] [Google Scholar]
  13. Ha-Kawa K., Hara J., Keiko Y., Muraguchi A., Kawamura N., Ishihara S., Doi S., Yabuuchi H. Kappa-chain gene rearrangement in an apparent T-lineage lymphoma. J Clin Invest. 1986 Dec;78(6):1439–1442. doi: 10.1172/JCI112733. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ha K., Hozumi N., Hrincu A., Gelfand E. W. Lineage specific classification of leukaemia: results of the analysis of sixty cases of childhood leukaemia. Br J Haematol. 1985 Oct;61(2):237–249. doi: 10.1111/j.1365-2141.1985.tb02822.x. [DOI] [PubMed] [Google Scholar]
  15. Haars R., Kronenberg M., Gallatin W. M., Weissman I. L., Owen F. L., Hood L. Rearrangement and expression of T cell antigen receptor and gamma genes during thymic development. J Exp Med. 1986 Jul 1;164(1):1–24. doi: 10.1084/jem.164.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hara J., Benedict S. H., Mak T. W., Gelfand E. W. T cell receptor alpha-chain gene rearrangements in B-precursor leukemia are in contrast to the findings in T cell acute lymphoblastic leukemia. Comparative study of T cell receptor gene rearrangement in childhood leukemia. J Clin Invest. 1987 Dec;80(6):1770–1777. doi: 10.1172/JCI113270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hara J., Kawa-Ha K., Yumura K., Ishihara S., Doi S., Yabuuchi H., Konishi S., Nishikawa A. Heterogeneity of acute undifferentiated leukemia at the immunoglobulin and T-cell receptor genes level. Jpn J Cancer Res. 1987 Feb;78(2):170–175. [PubMed] [Google Scholar]
  18. Karin M., Haslinger A., Holtgreve H., Cathala G., Slater E., Baxter J. D. Activation of a heterologous promoter in response to dexamethasone and cadmium by metallothionein gene 5'-flanking DNA. Cell. 1984 Feb;36(2):371–379. doi: 10.1016/0092-8674(84)90230-7. [DOI] [PubMed] [Google Scholar]
  19. Kleinfield R., Hardy R. R., Tarlinton D., Dangl J., Herzenberg L. A., Weigert M. Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphoma. 1986 Aug 28-Sep 3Nature. 322(6082):843–846. doi: 10.1038/322843a0. [DOI] [PubMed] [Google Scholar]
  20. Korsmeyer S. J., Arnold A., Bakhshi A., Ravetch J. V., Siebenlist U., Hieter P. A., Sharrow S. O., LeBien T. W., Kersey J. H., Poplack D. G. Immunoglobulin gene rearrangement and cell surface antigen expression in acute lymphocytic leukemias of T cell and B cell precursor origins. J Clin Invest. 1983 Feb;71(2):301–313. doi: 10.1172/JCI110770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Korsmeyer S. J., Hieter P. A., Ravetch J. V., Poplack D. G., Waldmann T. A., Leder P. Developmental hierarchy of immunoglobulin gene rearrangements in human leukemic pre-B-cells. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7096–7100. doi: 10.1073/pnas.78.11.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lefranc M. P., Rabbitts T. H. Two tandemly organized human genes encoding the T-cell gamma constant-region sequences show multiple rearrangement in different T-cell types. Nature. 1985 Aug 1;316(6027):464–466. doi: 10.1038/316464a0. [DOI] [PubMed] [Google Scholar]
  23. Littman D. R., Newton M., Crommie D., Ang S. L., Seidman J. G., Gettner S. N., Weiss A. Characterization of an expressed CD3-associated Ti gamma-chain reveals C gamma domain polymorphism. Nature. 1987 Mar 5;326(6108):85–88. doi: 10.1038/326085a0. [DOI] [PubMed] [Google Scholar]
  24. Maeda T., Sugiyama H., Tani Y., Miyake S., Oka Y., Ogawa H., Komori T., Soma T., Kishimoto S. Start of mu-chain production by the further two-step rearrangements of immunoglobulin heavy chain genes on one chromosome from a DJH/DJH configuration in an Abelson virus-transformed cell line: evidence of secondary DJH complex formation. J Immunol. 1987 Apr 1;138(7):2305–2310. [PubMed] [Google Scholar]
  25. Minden M. D., Toyonaga B., Ha K., Yanagi Y., Chin B., Gelfand E., Mak T. Somatic rearrangement of T-cell antigen receptor gene in human T-cell malignancies. Proc Natl Acad Sci U S A. 1985 Feb;82(4):1224–1227. doi: 10.1073/pnas.82.4.1224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mirro J., Jr, Kitchingman G., Behm F. G., Murphy S. B., Goorha R. M. T cell differentiation stages identified by molecular and immunologic analysis of the T cell receptor complex in childhood lymphoblastic leukemia. Blood. 1987 Mar;69(3):908–912. [PubMed] [Google Scholar]
  27. 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]
  28. Raulet D. H., Garman R. D., Saito H., Tonegawa S. Developmental regulation of T-cell receptor gene expression. Nature. 1985 Mar 7;314(6006):103–107. doi: 10.1038/314103a0. [DOI] [PubMed] [Google Scholar]
  29. Reth M., Gehrmann P., Petrac E., Wiese P. A novel VH to VHDJH joining mechanism in heavy-chain-negative (null) pre-B cells results in heavy-chain production. 1986 Aug 28-Sep 3Nature. 322(6082):840–842. doi: 10.1038/322840a0. [DOI] [PubMed] [Google Scholar]
  30. Royer H. D., Acuto O., Fabbi M., Tizard R., Ramachandran K., Smart J. E., Reinherz E. L. Genes encoding the Ti beta subunit of the antigen/MHC receptor undergo rearrangement during intrathymic ontogeny prior to surface T3-Ti expression. Cell. 1984 Dec;39(2 Pt 1):261–266. doi: 10.1016/0092-8674(84)90003-5. [DOI] [PubMed] [Google Scholar]
  31. Saito H., Kranz D. M., Takagaki Y., Hayday A. C., Eisen H. N., Tonegawa S. A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature. 1984 Nov 1;312(5989):36–40. doi: 10.1038/312036a0. [DOI] [PubMed] [Google Scholar]
  32. Saito H., Kranz D. M., Takagaki Y., Hayday A. C., Eisen H. N., Tonegawa S. Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. 1984 Jun 28-Jul 4Nature. 309(5971):757–762. doi: 10.1038/309757a0. [DOI] [PubMed] [Google Scholar]
  33. Sangster R. N., Minowada J., Suciu-Foca N., Minden M., Mak T. W. Rearrangement and expression of the alpha, beta, and gamma chain T cell receptor genes in human thymic leukemia cells and functional T cells. J Exp Med. 1986 Jun 1;163(6):1491–1508. doi: 10.1084/jem.163.6.1491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Shackelford D. A., Smith A. V., Trowbridge I. S. Changes in gene expression induced by a phorbol diester: expression of IL 2 receptor, T3, and T cell antigen receptor. J Immunol. 1987 Jan 15;138(2):613–619. [PubMed] [Google Scholar]
  35. Sim G. K., Yagüe J., Nelson J., Marrack P., Palmer E., Augustin A., Kappler J. Primary structure of human T-cell receptor alpha-chain. Nature. 1984 Dec 20;312(5996):771–775. doi: 10.1038/312771a0. [DOI] [PubMed] [Google Scholar]
  36. Snodgrass H. R., Dembić Z., Steinmetz M., von Boehmer H. Expression of T-cell antigen receptor genes during fetal development in the thymus. Nature. 1985 May 16;315(6016):232–233. doi: 10.1038/315232a0. [DOI] [PubMed] [Google Scholar]
  37. Snodgrass H. R., Kisielow P., Kiefer M., Steinmetz M., von Boehmer H. Ontogeny of the T-cell antigen receptor within the thymus. Nature. 1985 Feb 14;313(6003):592–595. doi: 10.1038/313592a0. [DOI] [PubMed] [Google Scholar]
  38. Tawa A., Benedict S. H., Hara J., Hozumi N., Gelfand E. W. Rearrangement of the T cell receptor gamma-chain gene in childhood acute lymphoblastic leukemia. Blood. 1987 Dec;70(6):1933–1939. [PubMed] [Google Scholar]
  39. Tawa A., Hozumi N., Minden M., Mak T. W., Gelfand E. W. Rearrangement of the T-cell receptor beta-chain gene in non-T-cell, non-B-cell acute lymphoblastic leukemia of childhood. N Engl J Med. 1985 Oct 24;313(17):1033–1037. doi: 10.1056/NEJM198510243131701. [DOI] [PubMed] [Google Scholar]
  40. Waldmann T. A., Davis M. M., Bongiovanni K. F., Korsmeyer S. J. Rearrangements of genes for the antigen receptor on T cells as markers of lineage and clonality in human lymphoid neoplasms. N Engl J Med. 1985 Sep 26;313(13):776–783. doi: 10.1056/NEJM198509263131303. [DOI] [PubMed] [Google Scholar]
  41. Yanagi Y., Chan A., Chin B., Minden M., Mak T. W. Analysis of cDNA clones specific for human T cells and the alpha and beta chains of the T-cell receptor heterodimer from a human T-cell line. Proc Natl Acad Sci U S A. 1985 May;82(10):3430–3434. doi: 10.1073/pnas.82.10.3430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yanagi Y., Yoshikai Y., Leggett K., Clark S. P., Aleksander I., Mak T. W. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature. 1984 Mar 8;308(5955):145–149. doi: 10.1038/308145a0. [DOI] [PubMed] [Google Scholar]
  43. Yancopoulos G. D., Alt F. W. Regulation of the assembly and expression of variable-region genes. Annu Rev Immunol. 1986;4:339–368. doi: 10.1146/annurev.iy.04.040186.002011. [DOI] [PubMed] [Google Scholar]
  44. Yoshikai Y., Anatoniou D., Clark S. P., Yanagi Y., Sangster R., Van den Elsen P., Terhorst C., Mak T. W. Sequence and expression of transcripts of the human T-cell receptor beta-chain genes. Nature. 1984 Dec 6;312(5994):521–524. doi: 10.1038/312521a0. [DOI] [PubMed] [Google Scholar]
  45. Yoshikai Y., Toyonaga B., Koga Y., Kimura N., Griesser H., Mak T. W. Repertoire of the human T cell gamma genes: high frequency of nonfunctional transcripts in thymus and mature T cells. Eur J Immunol. 1987 Jan;17(1):119–126. doi: 10.1002/eji.1830170120. [DOI] [PubMed] [Google Scholar]
  46. van Dongen J. J., Quertermous T., Bartram C. R., Gold D. P., Wolvers-Tettero I. L., Comans-Bitter W. M., Hooijkaas H., Adriaansen H. J., de Klein A., Raghavachar A. T cell receptor-CD3 complex during early T cell differentiation. Analysis of immature T cell acute lymphoblastic leukemias (T-ALL) at DNA, RNA, and cell membrane level. J Immunol. 1987 Feb 15;138(4):1260–1269. [PubMed] [Google Scholar]

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