Skip to main content
Log in

Chromosomal localization of HTLV-1 viral integration sites using in situ hybridization: detection of a novel IL2R fragment

  • Published:
Molecular and General Genetics MGG Aims and scope Submit manuscript

Summary

The presence of human T-cell leukemia virus (HTLV-1) in patients with adult T-cell leukemia (ATL) was investigated by Southern blotting and in situ hybridization. In all seven patients, HTLV-1 provirus was detected. A large and variable number of labeled restriction fragments were observed, indicating multiple integrations. Two of the patients analyzed by in situ hybridization had two, while the third patient had three, sites of viral integration on six different chromosomes, suggesting random integration. A single site of integration was shared by two patients, which was on chromosome 10 at bands p11→p15. One of these sites was on an apparently normal chromosome 10 and the other was on a derivative chromosome 10,t(10;14)(p12;g32). The interleukin 2 receptor (IL2R) has previously been localized to this region (10p14→p15). The α-chain of the IL2R is continuously expressed on affected T-cells in this disease. Southern blotting with pIL2R showed the presence of a novel 3.5 kb fragment in five out of the seven patients. This novel fragment has not been previously reported. No direct correlation was found between the novel 3.5 kb fragment, present in patients both cytogenetically normal and abnormal, and viral integration in the 10p11→p15 region in two patients. Therefore, it is suggested that the presence of the 3.5 kb fragment and the numerous chromosomal breaks associated with this disease may not be direct results of viral integration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Baer R, Heppell A, Taylor AMR, Rabbits PH, Boullier B, Rabbits TH (1987) The breakpoint of an inversion of chromosome 14 in a T-cell leukemia: Sequences downstream of the immuneglobulin heavy chain locus are implicated in tumorigenesis. Proc Natl Acad Sci USA 84:9069–9073

    Google Scholar 

  • Blattner WA, Kalyanaraman VS, Robert-Guroff M, Lister A, Galton DAG, Sarin PS, Crawford MH, Catousky D, Graves M, Gallo RC (1982) The human type-C retrovirus, HTLV in blacks from the Caribbean region and relationship to adult T-cell leukemia/lymphoma. Int J Cancer 30:257–264

    Google Scholar 

  • Boehm T, Rabbitts TH (1989) The human T-cell receptor genes are targets for chromosomal abnormalities in T-cell tumor. FASEB J 3:2344–2359

    Google Scholar 

  • Boehm T, Baer R, Lavenir I, Forster A, Waters JJ, Nacheva E, Rabbits TH (1988) The mechanism of chromosomal translocation t(11;14) involving the T-cell receptor CS locus on human chromosome 14g11 and a transcribed region of chromosome 11p15. EMBO J 7:385–394

    Google Scholar 

  • Brito-Babapalle V, Matutes E, Parreira L, Catousky D (1986) Abnormalities of chromosome 7q and Tac expression in T cell leukemias. Blood 67:516–521

    Google Scholar 

  • Champagne E, Takihara Y, Sagman U, deSousa J, Burrow S, Lewis WH, Mak TW, Minden MD (1989) The T-cell receptor Delta chain locus is disrupted in the T-ALL associated t(11;14)(p13;g11) translocation. Blood 73:1672–1676

    Google Scholar 

  • Chien YH, Iwashima M, Kaplan KB, Elliott JF, Davis MM (1987) A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. Nature 327:677–682

    Google Scholar 

  • Croce CM, Isobe M, Palumbo A, Puck J, Ming J, Tweardy D, Erikson J, Davis M, Rovera G (1985) Gene for α-chain of human T-cell receptor: Location on chromosome 14 region involved in T-cell neoplasms. Science 227:1044–1047

    Google Scholar 

  • Denny CT, Yoshikai Y, Mak TW, Smith SD, Hollis GF, Kirsch IR (1986) A chromosome 14 inversion in a T cell lymphoma is caused by site-specific recombination between immunolobulin and T-cell receptor loci. Nature 320:549–551

    Google Scholar 

  • Dubé ID, Raimondi SC, Pi D, Kalousek DK (1986) A new translocation, t(10:14)(g24;q11), in T cell neoplasia. Blood 67:1181–1184

    Google Scholar 

  • Erikson J, Finger L, Sun L, Ar-Rushdi A, Niskikura K, Minowada J, Finan J, Emanual BS, Nowell PC, Croce DM (1986) Deregulation of c-myc by translocation of the alpha-locus of the T-cell receptor in T-cell leukemias. Science 232:884–886

    Google Scholar 

  • Finger LR, Harvey RC, Moore RCA, Shower LC, Croce CM (1986) A common mechanism of chromosomal translocation in T- and B-cell neoplasia. Science 234:982–985

    Google Scholar 

  • Franchini G, Wong-Staal F, Gallo RC (1984) Human T-cell leukemia virus (HTLV-1) transcripts in fresh and cultured cells of patients with adult T-cell leukemia. Proc Natl Acad Sci USA 81:6207–6211

    Google Scholar 

  • Gallo RC (1984) Human T-cell leukemia/lymphoma virus and Tcell malignancies in adults. In: Franks LM, Weiss RA (eds) Cancer surveys, Vol 3 (1). Oxford University Press, Oxford, pp 113–159

    Google Scholar 

  • Gerhard DS, Kawasaki ES, Bancroft FC, Szabo P (1981) Localization of a unique gene by direct hybridization in situ. Proc Natl Acad Sci USA 78:3755–3759

    Google Scholar 

  • Gessain A, Gout O, Saal F, Daniel MT, Rio B, Flandrin G, Sigaux F, Lyon-Caen O, Peries J, de-The G (1990) Epidemiology and immunovirology of human T-cell leukemia/lymphoma virus type I-associated adult T-cell leukemia and chronic myelopathies as seen in France. Cancer Res 50:5692s-5696s

    Google Scholar 

  • Harvey RC, Marteneire C, Sun LHK, Williams D, Showe LC (1989) Translocations and rearrangements in T-cell acute leukemias with the t(11;14)(gl3;q11) chromosomal translocations. Oncogene 4:341–349

    Google Scholar 

  • Isobe M, Erikson J, Emanuel BS, Nowell PC, Croce CM (1985) Location of the gene for β subunit for human T-cell receptor at band 7835, a region prone to rearrangements in T-cells. Science 228:580–582

    Google Scholar 

  • Isobe M, Sadamori N, Russo G, Shimizu S, Yamamori S, Itoyama T, Yamada Y, Ikeda S, Ischimaru M, Kagan J, Croce CM (1990) Rearrangements in the human T-cell receptor a-chain locus in patients with adult T-cell leukemia carrying translocations involving chromosome 14g11. Cancer Res 50:6171–6175

    Google Scholar 

  • Itoyama T, Sadamori N, Tokunaga S, Sasagawa I, Nakamura H, Yao E-I, Jubashi T, Yamada Y, Ikeda S, Ichimaru M (1990) Cytogenetic studies of human T-cell leukemia virus type I carriers. Cancer Genet Cytogenet 49:157–163

    Google Scholar 

  • Kagan J, Finger LR, Letofsky J, Finan J, Nowell PC, Croce CM (1989) Clustering of breakpoints on chromosome 10 in acute T-cell leukemias with the t(10;14) chromosome translocation. Proc Natl Acad Sci USA 86:4161–4165

    Google Scholar 

  • Kamada N, Sakurai M, Miyamoto K, Sanada I, Sadamori N, Fukuhara S, Abe S, Shiraishi Y, Abe T, Kaneko Y, Shimoyama M (1992) Chromosome abnormalities in adult T-cell leukemia/ lymphoma: A karyotype review committee report. Cancer Res 52:1481–1493

    Google Scholar 

  • Kees UR, Lukeis R, Ford J, Garson OM (1989) Establishment and characterization of a childhood T-cell acute lymphoblastic leukemia cell line, ER-255, with chromosome abnormalities involving 7q 32–34 in association with T-cell receptor-β gene rearrangement. Blood 74:369–373

    Google Scholar 

  • Konishi H, Kobayashi N, Hatanaka M (1984) Defective human T-cell leukemia virus in adult T-cell leukemia patients. Mol Biol Med 2:273–283

    Google Scholar 

  • Kronke M, Leonard WJ, Depper JM, Greene WC (1985) Deregulation of interleukin-2 receptor gene expression in HTLV-1 induced adult T-cell leukemia. Science 228:1215–1217

    Google Scholar 

  • Lampert F, Harbott J, Ritterbach J, Ludwig W-D, Fonatsch C, Schuamborn D, Stier B, Gnekow A, Gerein V, Stollmann B, Jobke A, Janka-Schaub G (1988) T-cell acute childhood lymphoblastic leukemia with chromosome 14g11 anomaly; A morphologic, immunologic and cytogenetic analysis of 10 patients. Blut 56:117–123

    Google Scholar 

  • LeBeau MM, Diaz MO, Rowley JD, Mak TW (1985) Chromosomal localization of the human T cell receptor β chain genes. Cell 41:335

    Google Scholar 

  • LeBeau MM, McKeithan TW, Shima EA, Goldman-Leikin RE, Chan SJ, Bell GI, Rowley JD, Diaz O (1986) T-cell receptor α-chain gene is split in a human T-cell leukemia cell line with a t(11;14)(p15;g11). Proc Natl Acad Sci USA 83:9744–9748

    Google Scholar 

  • Leonard WJ, Depper JM, Crabtree GR, Rudikoff S, Pumphrey J, Robb RJ, Kronke M, Sevtlik PB, Peffer NJ, Waldmann TA, Greene WC (1984) Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature 311:626–631

    Google Scholar 

  • Leonard WJ, Donlon TA, Lebo RV, Greene WC (1985) Localization of the gene encoding the human interleukin-2 receptor on chromosome 10. Science 228:1547–1548

    Google Scholar 

  • Macera MJ, Szabo P, Verma RS (1989) A simple method for short term culturing bone marrow and unstimulated blood from acute leukemias. Leuk Res 13:729–734

    Google Scholar 

  • Maeda M, Shimiza A, Ikuta K, Okamoto H, Kashihara M, Uchiyama T, Honjo T, Yodoi J (1985) Origin of human T-lymphotrophic virus-I-positive T-cell lines in adult T-cell leukemia; analysis of T cell receptor gene rearrangement. J Exp Med 162:2169–2174

    Google Scholar 

  • Mathier-Mahul D, Caubert JF, Bernheim A, Mauchauffe M, Palmer E, Berger R, Larsen C-J (1985) Molecular cloning of a DNA fragment from human chromosome 14(14g11) involved in T-cell malignancies. EMBO J 4:3427–3433

    Google Scholar 

  • Matsuoka M, Hagiya M, Hattori T, Asou N, Maeda S, Shimada K, Tsai S, Sakano H, Takatsuki K (1988) Gene rearrangements of T-cell receptor β and δ chains in HTLV-1 infected primary neoplastic T-cells. Leukemia 2:84–90

    Google Scholar 

  • Mayall BH, Carrano AV, Moore DH, Ashworth LK, Bennett DE, Bogart E, Littlepage JL, Minkler JL, Piluso DE, Mendelson ML (1975) Cytophotometric analysis of human chromosomes. In: Mendelson ML (ed) Automation of cytogenetics. US Energy Research and Development Administration, Washington DC, p 133

    Google Scholar 

  • McBride OW, Battey J, Hollis GF, Swan DC, Siebenlist U, Leder P (1982) Localization of human variable and constant region immunoglobulin heavy chain genes on subtelomeric band q32 of chromosome 14. Nucleic Acids Res 10:8155–8170

    Google Scholar 

  • McKeithan TW, Shima EA, LeBeau MM, Minowada J, Rowley JD, Diaz MD (1986) Molecular cloning of the breakpoint junction of a human chromosomal 8;14 translocation involving the T-cell receptor alpha-chain gene and sequences on the 3′ side of MYC. Proc Natl Acad Sci USA 83:6636–6640

    Google Scholar 

  • Mengle-Gaw L, Willard HF, Smith CIE, Hammarstrom L, Fisher P, Sherrington P, Lucas G, Thompson PW, Baer R, Rabbits TH (1987) Human T-cell tumors containing chromosome 14 inversion or translocation with breakpoints proximal to immunoglobulin joining regions at 14q32. EMBO J 6:2273–2280

    Google Scholar 

  • Miyamoto K, Sato J, Kitajima K-I, Togaua A, Suemaru S, Sanada H, Tanaka T (1983) Adult T-cell leukemia. Chromosome analysis of 15 cases. Cancer 52:471–478

    Google Scholar 

  • Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtsuki Y, Shiraishi Y, Nagata K, Hinuma Y (1981) Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukemia T cells. Nature 294:770–771

    Google Scholar 

  • Mizutani S, Ford AM, Wiedeman LM, Chan LC, Furley AJW, Greaves MF, Molgaard HV (1986) Rearrangement of immunoglobulin heavy chain genes in human T-leukemic cells, preferential utilization of the D segment (DQ5 2) nearest to the J region. EMBO J 5:3467–3473

    Google Scholar 

  • Murre C, Waldman RA, Morton CC, Bongiovanni KF, Waldman TA, Shows TB, Seidman JG (1985) Human δ-chain genes are rearranged in leukemic T-cells and map to the short arm of chromosome 7. Nature 316:549–552

    Google Scholar 

  • Nosaka T, Kita K, Miwa H, Kawakami K, Ikeda T, Ohno T, Matsuoka N, Arita Y, Doi S, Nishikori M, Matsuda F, Lee KH, Shirakawa S, Honjo T, Hatanaka M (1989) Cross-lineage gene rearrangements in human leukemic B-precursor cells occur frequently with V-DJ rearrangements of IgH genes. Blood 74:361–368

    Google Scholar 

  • Nowell PC, Finan JB, Clark JW, Sarin PS, Gallo RC (1984) Karyotypic differences between primary cultures and cell lines from tumors with the human T-cell leukemia virus. J Natl Cancer Int 73:849–852

    Google Scholar 

  • Ohshima K, Yoshida T, Kikuchi M, Masuda Y, Kimura N, Satoh H (1990) Rerrangement of human T cell receptor β and δ chain genes in adult T cell leukemia/lymphoma. Hematol Oncol 8:111–118

    Google Scholar 

  • Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC (1980) Dection and isolation of type-C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA 77:7415–7419

    Google Scholar 

  • Popovic M, Wong-Staal F, Sarin PS, Gallo RC (1984) Biology of human T-cell leukemia-lymphoma virus (HTLV) Transformation of human T cells in vivo and in vitro. In: Klein G (ed) Advances in viral oncology, vol 4. Raven Press, New York, pp 45–70

    Google Scholar 

  • Rowley JD, Haren JM, Wong-Staal F, Franchini G, Gallo RC, Blattner W (1984) The chromosome pattern in cells from HTLV positive patients. In: Gallo RC, Essex M, Gross L (eds) Human T cell leukemia-lymphoma virus. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, pp 85–89

    Google Scholar 

  • Royer-Pokora B, Fleischer B, Ragg S, Loos U, Williams D (1989) Molecular cloning of the translocation breakpoint in T-ALL 11,14(p13;g11): genomic map of TCR alpha and delta region on chromosome 14q11 and long range map of region 11p13. Hum Genet 82:264–270

    Google Scholar 

  • Sadamori N, Nishino K, Kusano M, Tomonaga Y, Tagwa M, Yao E-I, Sasagawa I, Nakamura H, Ichimara M (1986) Significance of chromosome 14 anomaly at band 14g11 in Japanese patients with adult T-cell leukemia. Cancer 58:2244–2250

    Google Scholar 

  • Sadamori N, Isobe M, Shimizu S, Yamamori T, Itoyama T, Ikeda S, Yamada Y, Ichimaru M (1991) Relationship between chromosomal breakpoint and molecular rearrangement of T-cell antigen receptors in adult T-cell leukemia. Acta Haematol 86:14–19

    Google Scholar 

  • Sarin PS, Gallo RC (1983) Human T-cell leukemia-lymphoma virus (HTLV). In: Brown EB (ed) Progression hematology, vol XIII. Grime and Stratton, New York, pp 147–161

    Google Scholar 

  • Seiki M, Hattori S, Hirayama Y, Yoshida M (1983) Human adult T-cell leukemia virus: Complete nucleotide sequence of the provirus genome integrated in leukemia cell DNA. Proc Natl Acad Sci USA 80:3618–3622

    Google Scholar 

  • Seiki M, Eddy R, Shows TB, Yoshida M (1984) Nonspecific integration of the HTLV provirus genome into adult T-cell leukemia cells. Nature 309:640–642

    Google Scholar 

  • Shimoyama M, Abe T, Miyamoto K, Minato K, Tobinai K, Nagoshi H, Matsunaga M, Nomura T, Tsubota T, Ohnoshi T, Kimura I, Suemasu K (1987) Chromosome aberrations and clinical features of adult T-cell leukemia-lymphoma not associated with human T-cell leukemia virus type 1. Blood 69:984–989

    Google Scholar 

  • Smith MR, Greene WC (1991) Molecular biology of the type I human T-cell leukemia virus (HTLV-I) and adult T-cell leukemia. J Clin Invest 87:761–766

    Google Scholar 

  • Takatsuki KT, Uchiyama K, Sagawa K, Yodi J (1977) Adult T-cell leukemia in Japan. In: Series S, Takaka F, Irino S (eds) Topics in hematology. Excerpta Medica, Amsterdam, pp 73–77

    Google Scholar 

  • Toyonaga B, Mak TW (1986) Genes of the T-cell antigen receptor in normal and malignant T cells. Annu Rev Immunol 5:585–620

    Google Scholar 

  • Uchiyama T, Yodoi J, Segawa K, Takatsuki K, Uchino H (1977) Adult T-cell leukemia: Clinical and hematologic features of 16 cases. Blood 50:481–492

    Google Scholar 

  • Ueshima Y, Fukuhara S, Hattori T, Uchiyama T, Takatsuki K, Uchino H (1981) Chromosome studies in adult T-cell leukemia in Japan: Significance of trisomy 7. Blood 58:420–428

    Google Scholar 

  • Verma RS, Babu A (1989) Human Chromosomes: Manual of Basic Techniques. Pergamon Press, New York pp 7–9

    Google Scholar 

  • Verma RS, Macera MJ, Krishnamurthy M, Abramson J, Kapelner S, Dosik H (1987) Chromosomal abnormalities in adult T-cell leukemia/lymphoma (ATL). J Cancer Res Clin Oncol 113:192–196

    Google Scholar 

  • Wong-Staal F, Hahn B, Mangari V, Colombrin S, Franchini G, Gelman EP, Gallo RC (1983) A survey of human leukemias for sequences of a human retroviurs. Nature 302:626–628

    Google Scholar 

  • Yoshida M, Miyoshi I, Hinuma Y (1982) Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implications in the disease. Proc Natl Acad Sci USA 79:2031–2035

    Google Scholar 

  • Yoshida M, Seiki M, Yamaguchi K, Takatsuki K (1981) Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc Natl Acad Sci USA 81:2534–2537

    Google Scholar 

  • Yotte G, Schneider N, VanDyk L, Yang CY-C, Siciliano M, Buchanan G, Capra JD, Baer R (1989) The chromosome translocation (11;14)(g13;q11) associated with T-cell acute lymphotytic leukemia: An 11p13 breakpoint cluster region. Blood 74:374–379

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Macera, M.J., Szabo, P. & Verma, R.S. Chromosomal localization of HTLV-1 viral integration sites using in situ hybridization: detection of a novel IL2R fragment. Molec. Gen. Genet. 234, 466–474 (1992). https://doi.org/10.1007/BF00538707

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00538707

Key words

Navigation