Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Hypermethylation of the spleen tyrosine kinase promoter in T-lineage acute lymphoblastic leukemia

Oncogene volume 22, pages 2504–2514 (2003)Cite this article

Abstract

Sequence analysis of the noncoding first exon (exon 1) of the Syk gene demonstrated the presence of a previously cloned CpG island (GenBank #Z 65706). Transient transfection analysis in Daudi cells demonstrated promoter activity (18-fold increase over parental luciferase plasmid) for a 348 bp BstXI–BsrBI fragment containing this island. This region exhibits a high GC content (∼75%), contains several SP1 binding sites and a potential initiator sequence, but lacks a strong TATA consensus. Bisulfite sequencing and methylation-specific PCR (MSP) of this region demonstrated that the Syk promoter CpG island was largely unmethylated in B-lineage leukemia cell lines, control peripheral blood cells, human thymocytes and CD3+ T lymphocytes. However, dense methylation was seen in four T-lineage leukemia cell lines, Jurkat, H9, Molt 3 and HUT 78. MSP screening of leukemia cells from six T-lineage acute lymphoblastic leukemia (ALL) patients demonstrated methylation of the Syk promoter CpG island in one T-lineage ALL patient. Promoter methylation was correlated with reduced to absent expression of Syk mRNA and SYK protein in the T-lineage leukemia cell lines. Treatment of the leukemia lines Ha and Molt 3, with the methylation inhibitor, 5-aza-2′-deoxycytidine (5-aza-CdR) resulted in increased Syk mRNA expression. The presence of a methylated promoter sequence in these T-lineage leukemia cell lines and in one T-lineage patient suggests a potential role for SYK as a tumor suppressor in T-ALL.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Abbreviations

MSP:

methylation specific PCR

5-aza-CdR:

5-aza-2′-deoxycytidine

References

  • Akanuma D, Uzawa N, Yoshida MA, Negishi A, Amagasa T and Ikeuchi T . (1999). Oral Oncol., 35, 476–483.

  • Alcalay M and Toniolo D . (1988). Nucleic Acids Res., 16, 9527–9543

  • Antequera F, Boyes J and Bird A . (1990). Cell, 62, 503–514.

  • Ballestar E and Wolffe AP . (2001). Eur. J. Biochem., 268, 1–6.

  • Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP . (1998). Adv. Cancer Res., 72, 141–196.

  • Bird AP . (1986). Nature, 321, 209–213.

  • Birger Y, Shemer R, Perk J and Razin A . (1999). Nature, 397, 84–88.

  • Birnboim HC and Doly J . (1979). Nucleic Acids Res., 7, 1513–1523.

  • Bolen JB . (1995). Curr. Opin. Immunol., 7, 306–311.

  • Bolen JB and Brugge JS . (1997). Annu. Rev. Immunol., 15, 371–404.

  • Chan AC and Shaw AS . (1996). Curr. Opin. Immunol., 8, 394–401.

  • Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC, Clark EA and Weiss A . (1994). J. Immunol., 152, 4758–4766

  • Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB and Pawson T . (1995). Nature, 378, 303–306.

  • Chu DH, van Oers NS, Malissen M, Harris J, Elder M and Weiss A . (1999). J. Immunol., 163, 2610–2620.

  • Coopman PJ, Do MT, Barth M, Bowden ET, Hayes AJ, Basyuk E, Blancato JK, Vezza PR, McLeskey SW, Mangeat PH and Mueller SC . (2000). Nature, 406, 742–747.

  • Cornall RJ, Cheng AM, Pawson T and Goodnow CC . (2000). Proc. Natl. Acad. Sci. USA, 97, 1713–1718.

  • Craig NL . (1996). Curr. Top. Microbiol. Immunol., 204, 27–48.

  • Cross SH, Charlton JA, Nan X and Bird AP . (1994). Natl. Genet., 6, 236–244.

  • Deckert M, Tartare-Deckert S, Couture C, Mustelin T and Altman A . (1996). Immunity, 5, 591–604.

  • Dibirdik I, Kristupaitis D, Kurosaki T, Tuel-Ahlgren L, Chu A, Pond D, Tuong D, Luben R and Uckun FM . (1998). J. Biol. Chem., 273, 4035–4039.

  • Dodge JE, List AF and Futscher BW . (1998). Int. J. Cancer, 78, 561–567.

  • Feinberg AP and Vogelstein B . (1983). Anal. Biochem., 132, 6–13.

  • Flatau E, Bogenmann E and Jones PA . (1983). Cancer Res., 43, 4901–4905.

  • Gardiner-Garden M and Frommer M . (1987). J. Mol., Biol., 196, 261–282.

  • Glavac D, Ravnik-Glavac M, Ovcak Z and Masera A . (1996). Pflugers Arch., 431, R193–R194.

  • Goodman PA, Juran B, Wood CM and Uckun FM . (2002). Leukemia Lymphoma, 43, 627–635.

  • Goodman PA, Niehoff LB and Uckun FM . (1998). J. Biol. Chem., 273, 17742–17748.

  • Goodman PA, Wood CM, Vassilev A, Mao C and Uckun FM . (2001). Oncogene, 20, 3969–3978.

  • Gootenberg JE, Ruscetti FW, Mier JW, Gazdar A and Gallo RC . (1981). J. Exp. Med., 154, 1403–1418.

  • Gulbins E, Langlet C, Baier G, Bonnefoy-Berard N, Herbert E, Altman A and Coggeshall KM . (1994). J. Immunol., 152, 2123–2129.

  • Guo SX, Taki T, Ohnishi H, Piao HY, Tabuchi K, Bessho F, Hanada R, Yanagisawa M and Hayashi Y . (2000). Leukemia Res., 24, 39–46.

  • Harmer SL and DeFranco AL . (1997). Mol. Cell Biol., 17, 4087–4095.

  • Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM et al. (1994). Proc. Natl. Acad. Sci. USA, 91, 9700–9704.

  • Jones PA . (1996). Cancer Res., 56, 2463–2467.

  • Jones PA and Laird PW . (1999). Nat. Genet., 21, 163–167.

  • Jost JP and Hofsteenge J . (1992). Proc. Natl. Acad. Sci. USA, 89, 9499–9503.

  • Kass SU, Pruss D and Wolffe AP . (1997). Trends Genet., 13, 444–449.

  • Koeffler HP and Golde DW . (1980). Blood, 56, 344–350.

  • Kurosaki T, Johnson SA, Pao L, Sada K, Yamamura H and, Cambier JC . (1995). J. Exp. Med., 182, 1815–1823.

  • Larsen F, Gundersen G, Lopez R and Prydz H . (1992). Genomics, 13, 1095–1107.

  • Latour S, Chow LML and Veillette A . (1996). J. Biol. Chem., 271, 22782–22790.

  • Law CL, Chandran KA, Sidorenko SP and Clark EA . (1996). Mol. Cell Biol., 16, 1305–1315.

  • Li HL, Forman MS, Kurosaki T and Pure E . (1997). J. Biol. Chem., 272, 18200–18208.

  • Lozzio BB and Lozzio CB . (1979). Leukemia Res., 3, 363–370.

  • Lozzio BB, Lozzio CB, Bamberger EG and Feliu AS . (1981). Proc. Soc. Exp. Biol. Med., 166, 546–550.

  • Mahajan S, Fargnoli J, Burkhardt AL, Kut SA, Saouaf SJ and Bolen JB . (1995). Mol. Cell. Biol., 15, 5304–5311.

  • Mallick-Wood CA, Pao W, Cheng AM, Lewis JM, Kulkarni S, Bolen JB, Rowley B, Tigelaar RE, Pawson T and Hayday AC . (1996). Proc. Natl. Acad. Sci. USA, 93, 9704–9709.

  • Mann DL, O'Brien SJ, Gilbert DA, Reid Y, Popovic M, Read-Connole E, Gallo RC and Gazdar AF . (1989). AIDS Res. Hum. Retroviruses, 5, 253–255.

  • Minowada J, Onuma T and Moore GE . (1972). J. Natl. Cancer Institute, 49, 891–895.

  • Minowada J, Koshiba H, Sagawa K, Kubonishi I, Lok MS, Tatsumi E, Han T, Srivastava BI and Ohnuma T . (1981). Cancer Res. Clin. Oncol., 101, 91–100.

  • Nagai K, Takata M, Yamamura H and Kurosaki T . (1995). J. Biol. Chem., 270, 6824–6829.

  • Neuhausen SL, Swensen J, Miki Y, Liu Q, Tavtigian S, Shattuck-Eidens D, Kamb A, Hobbs MR, Gingrich J and Shizuya H. (1994). Hum. Mol. Genet., 3, 1919–1926.

  • Ng HH and Bird A . (2000). Trend Biochem. Sci., 25, 121–126.

  • Okamura S, Ng CC, Koyama K, Takei Y, Arakawa H, Monden M and Nakamura Y . (1999). Oncol. Res., 11, 281–285.

  • Panchamoorthy G, Fukazawa T, Miyake S, Soltoff S, Reedquist K, Druker B, Shoelson S, Cantley L and Band H . (1996). J. Biol. Chem., 271, 3187–3194.

  • Pawlak A, Bryans M and Jost JP . (1991). Nucleic Acids Res., 19, 1029–1034.

  • Qin S, Ding J, Kurosaki T and Yamamura H . (1998). FEBS Lett., 427, 139–143.

  • Razin A and Cedar H . (1991). Microbiol. Rev., 55, 451–458.

  • Shepherd NS, Pfrogner BD, Coulby JN, Ackerman SL, Vaidyanathan G, Sauer RH, Balkenhol TC and Sternberg N . (1994). Proc. Natl. Acad. Sci. USA, 91, 2629–2633.

  • Sidorenko SP, Law CL, Chandran KA and Clark EA . (1995). Proc. Natl. Acad. Sci. USA, 92, 359–363.

  • Sieh M, Batzer A, Schlessinger J and Weiss A . (1994). Mol. Cell. Biol., 14, 4435–4442.

  • Smiraglia DJ, Rush LJ, Fruhwald MC, Dai Z, Held WA, Costello JF, Lang JC, Eng C, Li B, Wright FA, Caligiuri MA and Plass C . (2001). Hum. Mol. Genet., 10, 1413–1419.

  • Stellwagen AE and Craig NL . (1997). EMBO J., 16, 6823–6834.

  • Sternberg NL . (1992). Trends Genet., 8, 11–16.

  • Stewart ZA and Pietenpol JA . (2001). Breast Cancer Res., 3, 5–7.

  • Stirzaker C, Millar DS, Paul CL, Warnecke PM, Harrison J, Vincent PC, Frommer M and Clark SJ . (1997). Cancer Res., 57, 2229–2237.

  • Takata M and Kurosaki T . (1996). J. Exp. Med., 184, 31–40.

  • Takata M, Sabe H, Hata A, Inazu T, Homma Y, Nukada T, Yamamura H and Kurosaki T . (1994). EMBO J., 13, 1341–1349.

  • Tate PH and Bird AP . (1993). Curr. Opin. Genet. Dev., 3, 226–231.

  • Tibbles HE, Vassilev A, Wendorf H, Schonhoff D, Zhu D, Lorenz D, Waurzyniak B, Liu XP and Uckun FM . (2001). J. Biol. Chem., 276, 17815–17822.

  • Turner M, Gulbranson-Judge A, Quinn ME, Walters AE, MacLennan IC and Tybulewicz VL . (1997). J. Exp. Med., 186, 2013–2021.

  • Uckun FM, Gaynon P, Sather H, Arthur D, Trigg M, Tubergen D, Nachman J, Steinherz P, Sensel MG and Reaman GR . (1997). Blood, 89, 2488–2493.

  • Uckun FM, Muraguchi A, Ledbetter JA, Kishimoto T, O'Brien RT, Roloff JS, Gajl-Peczalska K, Provisor A and Koller B . (1989). Blood, 73, 1000–1015.

  • Uckun FM, Schieven GL, Dibirdik I, Chandan-Langlie M, Tuel-Ahlgren L and Ledbetter JA . (1991). J. Biol. Chem., 266, 17478–17485.

  • Uckun FM, Tuel-Ahlgren L, Song CW, Waddick K, Myers DE, Kirihara J, Ledbetter JA and Schieven GL . (1992). Proc. Natl. Acad. Sci. USA, 89, 9005–9009

  • Uckun FM, Tuel-Ahlgren L, Waddick KG, Jun X, Jin J, Myers DE, Rowley RB, Burkhardt AL and Bolen JB . (1996a). J. Biol. Chem., 271, 6389–6397.

  • Uckun FM, Vallera DA and Wee SL . (1985). J. Immunol., 1135, 3817–3822.

  • Uckun FM, Waddick KG, Mahajan S, Jun X, Takata M, Bolen J and Kurosaki T . (1996b). Science, 273, 1096–1100.

  • van den Hoff MJ, Moorman AF and Lamers WH . (1992). Nucleic Acids Res., 20, 2902.

  • Vassilev A, Ozer Z, Navara C, Mahajan S and Uckun FM . (1999). J. Biol. Chem., 274, 1646–1656.

  • Yeivin A and Razin A . (1993). Exs. (Experientia Supplementa), 64, 523–568.

  • Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T and Hirohashi S . (1995). Proc. Natl. Acad. Sci. USA, 92, 7416–7419.

  • Yuan Y, Mendez R, Sahin A and Dai JL . (2001). Cancer Res., 61, 5558–5561.

  • Zhang XY, Jabrane-Ferrat N, Asiedu CK, Samac S, Peterlin BM and Ehrlich M . (1993). Mol. Cell. Biol., 13, 6810–6818.

Download references

Acknowledgements

We thank Alexei Vassilev and Zahide Ohzer for their helpful advice and assistance. We also thank Elizabeth Bockman and Steve Bartell for their technical assistance.

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, Parker Hughes Institute and Parker Hughes Cancer Center, 2699 Patton Road, St Paul, 55113, MN, USA

    Patricia A Goodman, Nicole Burkhardt & Brian Juran

  2. Department of Biochemistry, Parker Hughes Institute and Parker Hughes Cancer Center, 2699 Patton Road, St Paul, 55113, MN, USA

    Heather E Tibbles

  3. Department of Molecular Oncology, Parker Hughes Institute and Parker Hughes Cancer Center, 2699 Patton Road, St Paul, 55113, MN, USA

    Faith M Uckun

Authors
  1. Patricia A Goodman
    View author publications

    Search author on:PubMed Google Scholar

  2. Nicole Burkhardt
    View author publications

    Search author on:PubMed Google Scholar

  3. Brian Juran
    View author publications

    Search author on:PubMed Google Scholar

  4. Heather E Tibbles
    View author publications

    Search author on:PubMed Google Scholar

  5. Faith M Uckun
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Faith M Uckun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goodman, P., Burkhardt, N., Juran, B. et al. Hypermethylation of the spleen tyrosine kinase promoter in T-lineage acute lymphoblastic leukemia. Oncogene 22, 2504–2514 (2003). https://doi.org/10.1038/sj.onc.1206313

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/sj.onc.1206313

Keywords

This article is cited by

Search

Advanced search

Quick links