Tumor Biology

, Volume 36, Issue 11, pp 8317–8324 | Cite as

Telomere shortening associated with increased genomic complexity in chronic lymphocytic leukemia

  • Patricia Dos Santos
  • Julieta Panero
  • Virginia Palau Nagore
  • Carmen Stanganelli
  • Raimundo F. Bezares
  • Irma Slavutsky
Research Article

Abstract

Telomeric dysfunction has been proposed as an emerging prognostic factor in chronic lymphocytic leukemia (CLL). We have explored the relationship between telomere length (TL) and chromosome alterations studied by fluorescence in situ hybridization (FISH) and conventional cytogenetics in 107 newly diagnosed CLL patients; 61 normal controls were also evaluated. Results were correlated with clinical parameters and outcome. Absolute TL measurement was carried out on DNA samples by real-time quantitative PCR. A significant telomere shortening in patients compared to controls was observed (p = 0.0001). The analysis taking into account FISH risk groups showed shorter TLs in cases with del11q/17p compared to patients with 13q14 deletion as a single alteration (p = 0.0037), no alterations (NA) (p = 0.028), and cases with abnormal karyotypes (p = 0.014). In addition, a significant TL reduction in cases with two or more anomalies with respect to those with NA (p = 0.033) and with one alteration (p = 0.045), and no differences compared to cases with deletions 11q/17p were observed. Patients with only one anomaly did not show statistical differences with respect to controls; meanwhile, a significant TL reduction in cases with two or more aberrations was observed (p = 0.025). The shortest telomeres were associated to 11q/17p deletion with significant differences compared to the remaining groups (p ≤ 0.045). Significantly shorter treatment free survival in patients with two or more alterations compared to those with NA plus one abnormality was observed (p = 0.0006). Our findings support the association between short TL and chromosome alterations in CLL and indicate the importance of telomere dysfunction in driving genomic instability in this pathology.

Keywords

Chronic lymphocytic leukemia Telomere length FISH Cytogenetics 

Notes

Acknowledgments

This work was supported by grants from the National Research Council (CONICET) (PIP N°: 517), the National Agency of Scientific and Technical Promotion (ANPCyT) (PICT No: 2008–0465), and the Alberto J. Roemmers Foundation.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the Institutional Research Committee and with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individuals included in the study.

Conflicts of interest

None

Supplementary material

13277_2015_3556_MOESM1_ESM.docx (12 kb)
Table S1 (DOCX 11 kb)
13277_2015_3556_Fig6_ESM.gif (75 kb)
ESM 1

(GIF 75 kb)

13277_2015_3556_MOESM2_ESM.tif (133 kb)
High resolution image (TIFF 132 kb)

References

  1. 1.
    Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. New Eng J Med. 2005;352:804–15.CrossRefPubMedGoogle Scholar
  2. 2.
    Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–34.PubMedGoogle Scholar
  3. 3.
    Binet JL, Lepoprier M, Dighiero G, Charron D, D’Athis P, Vaugier G, et al. A clinical staging system for chronic lymphocytic leukemia: prognostic significance. Cancer. 1977;40:855–64.CrossRefPubMedGoogle Scholar
  4. 4.
    Chiorazzi N. Implications of new prognostic markers in chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Program. 2012;2012:76–87.Google Scholar
  5. 5.
    Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Eng J Med. 2000;343:1910–6.CrossRefGoogle Scholar
  6. 6.
    Mayr C, Speicher MR, Kofler DM, Buhmann R, Strehl J, Busch R, et al. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood. 2006;107:742–51.CrossRefPubMedGoogle Scholar
  7. 7.
    Haferlach C, Dicker F, Schnittger S, Kern W, Haferlach T. Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping. Leukemia. 2007;21:2442–51.CrossRefPubMedGoogle Scholar
  8. 8.
    Travella A, Ripollés L, Aventin A, Rodríguez A, Bezares RF, Caballín MR, et al. Structural alterations in chronic lymphocytic leukaemia. Cytogenetic and FISH analysis. Hematol Oncol. 2013;31:339–47.CrossRefGoogle Scholar
  9. 9.
    Gisselsson D, Jonson T, Petersén A, Strömbeck B, Dal Cin P, Höglund M, et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci U S A. 2001;98:12683–8.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Deng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer. 2008;8:450–8.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ricca I, Rocci A, Drandi D, Francese R, Compagno M, Lobetti Bodoni C, et al. Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients. Leukemia. 2007;21:697–705.PubMedGoogle Scholar
  12. 12.
    Roos G, Kröber A, Grabowski P, Kienle D, Bühler A, Döhner H, et al. Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia. Blood. 2008;111:2246–52.CrossRefPubMedGoogle Scholar
  13. 13.
    Rossi D, Lobetti Bodoni C, Genuardi E, Monitillo L, Drandi D, Cerri M, et al. Telomere length is an independent predictor of survival, treatment requirement and Richter’s syndrome transformation in chronic lymphocytic leukemia. Leukemia. 2009;23:1062–72.CrossRefPubMedGoogle Scholar
  14. 14.
    Rampazzo E, Bonaldi L, Trentin L, Visco C, Keppel S, Giunco S, et al. Telomere length and telomerase levels delineate subgroups of B-cell chronic lymphocytic leukemia with different biological characteristics and clinical outcomes. Haematologica. 2012;97:56–63.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sellman L, de Beer D, Bartels M, Opalka B, Nückel H, Dührsen U, et al. Telomeres and prognosis in patients with chronic lymphocytic leukemia. Int J Hematol. 2011;93:74–82.CrossRefGoogle Scholar
  16. 16.
    Rossi D, Cerri M, Capello D, Deambrogi C, Rossi FM, Zucchetto A, et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol. 2008;142:202–15.CrossRefPubMedGoogle Scholar
  17. 17.
    Mansouri L, Grabowski P, Degerman S, Svenson U, Gunnarsson R, Cahill N, et al. Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients. Am J Hematol. 2013;88:647–51.CrossRefPubMedGoogle Scholar
  18. 18.
    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Panero J, O’Callaghan NJ, Fenech M, Slavutsky I. Absolute qPCR for measuring telomere length in bone marrow samples of plasma cell disorders. Mol Biotechnol. 2015;57:155–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Grabowski P, Hultdin M, Karlsson K, Tobin G, Aleskog A, Thunberg U, et al. Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status. Blood. 2005;105:4807–12.CrossRefPubMedGoogle Scholar
  21. 21.
    Cottliar A, Pedrazzini E, Corrado C, Engelberger MI, Narbaitz M, Slavutsky I. Telomere shortening in patients with plasma cell disorders. Eur J Haematol. 2003;71:334–40.CrossRefPubMedGoogle Scholar
  22. 22.
    Hoxha M, Fabris S, Agnelli L, Bollati V, Cutrona G, Matis S, et al. Relevance of telomere/telomerase system impairment in early stage chronic lymphocytic leukemia. Genes Chrom Cancer. 2014;53:612–21.CrossRefPubMedGoogle Scholar
  23. 23.
    Lin K-H, Yan J. The telomere length dynamic and methods of its assessment. J Cell Mol Med. 2005;9:977–89.CrossRefPubMedGoogle Scholar
  24. 24.
    Lin TT, Letsolo BT, Jones RE, Rowson J, Pratt G, Hewamana S, et al. Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis. Blood. 2010;116:1899–907.CrossRefPubMedGoogle Scholar
  25. 25.
    Jones CH, Pepper C, Baird DM. Telomere dysfunction and its role in haematological cancer. Br J Haematol. 2012;156:573–87.CrossRefPubMedGoogle Scholar
  26. 26.
    Wu KD, Orme LM, Shaughnessy Jr J, Jacobson J, Barlogie B, Moore MA. Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival. Blood. 2003;101:4982–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Cottliar AS, Panero J, Pedrazzini E, Noriega MF, Narbaitz M, Rodríguez A, et al. Analysis of telomere length in mantle cell lymphoma. Eur J Haematol. 2009;83:433–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Chelliat Jebaraj BM, Kienle D, Lechel A, Mertens D, Heuberger M, Ott G, et al. Telomere length in mantle cell lymphoma. Blood. 2013;121:1184–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Van Den Neste E, Robin V, Francart J, Hagemeijer A, Stul M, Vandenberghe P, et al. Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine. Leukemia. 2007;21:1715–22.CrossRefGoogle Scholar
  30. 30.
    Augereau A, de Roodenbeke T’k, Simonet T, Bauwens S, Horard B, Callanan M, et al. Telomeric damage in early stage of chronic lymphocytic leukemia correlates with shelterin dysregulation. Blood. 2011;118:1316–22.CrossRefPubMedGoogle Scholar
  31. 31.
    Lin TT, Norris K, Heppel NH, Pratt G, Allan JM, Allsup DJ, et al. Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. Br J Haematol. 2014;167:214–23.CrossRefPubMedGoogle Scholar
  32. 32.
    Kienle DL, Korz C, Hosch B, Benner A, Mertens D, Habermann A, et al. Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes. J Clin Oncol. 2005;23:3780–92.CrossRefPubMedGoogle Scholar
  33. 33.
    Brugat T, Nguyen-Khac F, Grelier A, Merle-Béral H, Delic J. Telomere dysfunction-induced foci arise with the onset of telomeric deletions and complex chromosomal aberrations in resistant chronic lymphocytic leukemia cells. Blood. 2010;116:239–49.CrossRefPubMedGoogle Scholar
  34. 34.
    Rigolin GM, Cibien F, Martinelli S, Formigaro L, Rizzotto L, Tammiso E, et al. Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with “normal” FISH: correlations with clinicobiologic parameters. Blood. 2012;119:2310–3.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Patricia Dos Santos
    • 1
  • Julieta Panero
    • 1
  • Virginia Palau Nagore
    • 1
  • Carmen Stanganelli
    • 2
  • Raimundo F. Bezares
    • 3
  • Irma Slavutsky
    • 1
  1. 1.Laboratorio de Genética de Neoplasias LinfoidesInstituto de Medicina Experimental, CONICET-Academia Nacional de MedicinaBuenos AiresArgentina
  2. 2.División Patología MolecularInstituto de Investigaciones Hematológicas, Academia Nacional de MedicinaBuenos AiresArgentina
  3. 3.Servicio de HematologíaHospital General de Agudos “Dr Teodoro Álvarez”Buenos AiresArgentina

Personalised recommendations