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:

Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia

Oncogene volume 24, pages 7213–7223 (2005)Cite this article

A Retraction to this article was published on 07 February 2013

Abstract

Aberrant genome-wide hypomethylation is thought to be related to tumorigenesis by promoting genomic instability. Since DNA methylation is considered an important mechanism for the silencing of retroelements, hypomethylation in human tumors may lead to their reactivation. However, the role of DNA hypomethylation in chronic myeloid leukemia (CML) remains to be elucidated. In this study, the methylation status of the LINE-1 (L1) retrotransposon promoter was analysed in CML samples from the chronic-phase (CP, n=140) and the blast crisis (BC, n=47). L1 hypomethylation was significantly more frequent in BC (74.5%) than in CP (38%) (P<0.0001). Furthermore, L1 hypomethylation led to activation of both ORF1 sense transcription (P<0.0001) and c-MET gene antisense transcription (P<0.0001), and was significantly associated with high levels of BCR–ABL (P=0.02) and DNMT3b4 (P=0.001) transcripts. Interestingly, in CP-CML, extensive L1 hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (P=0.004) or imatinib (P=0.034) and progression-free survival (P=0.005). The above results strongly suggest that activation of both sense and antisense transcriptions by aberrant promoter hypomethylation of the L1 elements plays a role in the progression and clinical behavior of the CML.

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

Access options

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
Figure 7
Figure 8

Similar content being viewed by others

References

  • Birchmeier C, Birchmeier W, Gherardi E and Vande-Woude GF . (2003). Nat. Rev. Mol. Cell. Biol., 4, 915–925.

  • Bratthauer GL and Fanning TG . (1992). Oncogene, 7, 507–510.

  • Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV and Kazazian HH . (2003). Proc. Natl. Acad. Sci. USA, 100, 5280–5285.

  • Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ and Lydon NB . (2000). J. Pharmacol. Exp. Ther., 295, 139–145.

  • Calabretta B and Perrotti D . (2004). Blood, 103, 4010–4022.

  • Chen RZ, Pettersson U, Beard C, Jackson-Grusby L and Jaenisch R . (1998). Nature, 395, 89–93.

  • Christensen JG, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, Chen J, Wang X, Ruslim L and Blake R . (2003). Cancer Res., 63, 7345–7355.

  • Comoglio PM . (2001). Nat. Cell. Biol., 3, 161–162.

  • Dante R, Dante-Paire J, Rigal D and Roizes G . (1992). Anticancer Res., 12, 559–563.

  • Deininger PL and Batzer MA . (2002). Genome Res., 12, 1455–1465.

  • Deutsch E, Dugray A, AbdulKarim B, Marangoni E, Maggiorella L, Vaganay S, M'Kacher R, Rasy SD, Eschwege F and Vainchenker W . (2001). Blood, 97, 2084–2090.

  • Deutsch E, Jarrousse S, Buet D, Dugray A, Bonnet ML, Vozenin-Brotons MC, Guilhot F, Turhan AG, Feunteun J and Bourhis J . (2003). Blood, 101, 4583–4588.

  • Eden A, Gaudet F, Waghmare A and Jaenisch R . (2003). Science, 300, 455.

  • Emig M, Saussele S, Wittor H, Weisser A, Reiter A, Willer A, Berger U, Hehlmann R, Cross NC and Hochhaus A . (1999). Leukemia, 13, 1825–1832.

  • Feng Q, Moran JV, Kazazian HH and Boeke JD . (1996). Cell, 87, 905–916.

  • Florl AR, Lower R, Schmitz-Drager BJ and Schutz W . (1999). Br. J. Cancer, 80, 1312–1321.

  • Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H and Jaenisch R . (2003). Science, 300, 489–492.

  • Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL and Ansari H . (1998). J. Natl. Cancer Inst., 90, 850–858.

  • Hermann JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB . (1996). Proc. Natl. Acad. Sci. USA, 93, 9821–9826.

  • Higumann P, Redik K, Matlik K and Speek M . (2002). Genomics, 79, 628–634.

  • Huntly BJ, Bench A and Green AR . (2003). Blood, 102, 1160–1168.

  • Kantarjian HM, Keating MJ, Smith TL, Talpaz M and McCredie KB . (1999). Am. J. Med., 88, 1–8.

  • Kazazian HH and Moran JV . (1998). Nat. Genet., 19, 19–20.

  • Lengauer C, Kinzler KW and Vogelstein B . (1997). Proc. Natl. Acad. Sci. USA, 94, 2545–2550.

  • Lin CH, Hsieh SY, Sheen IS, Lee WC, Chen TC, Shyu WC and Liaw YF . (2001). Cancer Res., 61, 4238–4243.

  • Liu J, Nau MM, Zucman-Rossi J, Powell JI, Allegra CJ and Wright JJ . (1997). Genes Chromosom. Cancer, 18, 232–239.

  • Ma PC, Maulik G, Christensen J and Salgia R . (2003). Cancer Metast. Rev., 22, 309–325.

  • Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT and Salgia R . (2002). Cytokine Growth Factor Rev., 13, 41–59.

  • Menendez L, Benigno BB and McDonald JF . (2004). Mol. Cancer, 3, 12–17.

  • Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J, Kinzler KW, Vogelstein B and Nakamura Y . (1992). Cancer Res., 52, 643–645.

  • Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y and Sasaki H . (2001). Blood, 97, 1172–1179.

  • Morse B, Rotherg PG, South VJ, Spandorfer JM and Astrin SM . (1988). Nature, 333, 87–90.

  • Nagarajan L, Lange B, Cannizzaro L, Finan J, Nowell PC and Huebner K . (1990). Blood, 75, 82–87.

  • Ovchinnikov I, Rubin A and Swergold GD . (2002). Proc. Natl. Acad. Sci. USA, 99, 10522–10527.

  • Pomykala HM, Bohlander SK, Broeker PL, Olopade OI and Diaz MO . (1994). Mol. Cell. Biol., 14, 7604–7610.

  • Prak ETL and Kazazian HH . (2000). Nat. Rev., 1, 134–144.

  • Rizwana R and Hahn PJ . (1999). J. Cell. Sci., 112, 4513–4519.

  • Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H and Hirohashi S . (2002). Proc. Natl. Acad. Sci. USA, 99, 10060–10065.

  • Santourlidis S, Florl A, Ackermann R, Wirtz HC and Schulz WA . (1999). Prostate, 39, 166–174.

  • Shet AS, Jahagirdar BN and Verfaillie CM . (2002). Leukemia, 16, 1402–1411.

  • Schulz WA, Elo JP, Florl AR, Pennanen S, Santourlidis S, Engers R, Buchardt M, Seifert HH and Visakorpi T . (2002). Gene Chromosom. Cancer, 35, 58–65.

  • Slupianek A, Schmutte C, Tombline G, Nieborowska-Skorska M, Hoser G, Nowicki MO, Pierce AJ, Fishel R and Skorski T . (2001). Mol. Cell., 8, 795–806.

  • Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, Tso CY, Braun TJ, Clarkson BD and Cervantes F . (1984). Blood, 63, 789–799.

  • Speek M . (2001). Mol. Cell. Biol., 21, 1973–1985.

  • Suter CM, Martin DI and Ward RL . (2004). Int. J. Colorect. Dis., 19, 95–101.

  • Takai D, Yagi Y, Habib N, Sugimura T and Ushijima T . (2000). Jpn. J. Clin. Oncol., 30, 306–309.

  • Wong N, Lam WC, Lai PB, Pang E, Lau WY and Johnson PJ . (2001). Am. J. Pathol., 159, 465–471.

  • Woodcock DM, Lawler CB, Linsenmeyer MK, Doherty JP and Warren WD . (1997). J. Biol. Chem., 272, 7810–7816.

  • Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ and Viegas-Pequignot E . (1999). Nature, 402, 187–191.

  • Yoder JA, Walsh CP and Bestor TH . (1997). Trends Genet., 13, 335–340.

  • Yu F, Zingler N, Schumann G and Stratling WH . (2001). Nucleic Acids Res., 29, 4493–4501.

Download references

Acknowledgements

This work was supported by grants from Fondo de Investigacion Sanitaria (FIS, Spain) 03/0141, 01/0013-01, 01/F018, 02/1299; Navarra Goverment (31/2002); RETIC C03/10, Junta de Andalucia 03/143; 03/144, and funds from Cajamar-Fundacion Hospital Carlos Haya (IMABIS, Malaga, Spain), ‘UTE project CIMA’, Fundación de Investigación Médica Mutua Madrileña Automovilista and Asociacion Medicina e Investigacion (AMI).

Author information

Authors and Affiliations

  1. Hematology Department, Reina Sofia Hospital, Avda. Menendez Pidal s/n. 14004, Cordoba, Spain

    Jose Roman-Gomez, Joaquin Sanchez, Juan A Castillejo & Antonio Torres

  2. Hematology Department, Carlos Haya Hospital, Malaga, Spain

    Antonio Jimenez-Velasco, Manuel Barrios, German Navarro & Anabel Heiniger

  3. Hematology Department, Cellular Therapy Area, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain

    Xabier Agirre, Leire Garate & Felipe Prosper

  4. Hematology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain

    Francisco Cervantes & Dolors Colomer

Authors
  1. Jose Roman-Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Jimenez-Velasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xabier Agirre
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francisco Cervantes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joaquin Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leire Garate
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Manuel Barrios
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Juan A Castillejo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. German Navarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dolors Colomer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Felipe Prosper
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anabel Heiniger
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Antonio Torres
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose Roman-Gomez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roman-Gomez, J., Jimenez-Velasco, A., Agirre, X. et al. Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia. Oncogene 24, 7213–7223 (2005). https://doi.org/10.1038/sj.onc.1208866

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208866

Keywords

Search

Advanced search

Quick links