Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults1,2,3. We have analyzed exome sequencing data from 127 individuals with CLL and Sanger sequencing data from 214 additional affected individuals, identifying recurrent somatic mutations in POT1 (encoding protection of telomeres 1) in 3.5% of the cases, with the frequency reaching 9% when only individuals without IGHV@ mutations were considered. POT1 encodes a component of the shelterin complex and is the first member of this telomeric structure found to be mutated in human cancer. Somatic mutation of POT1 primarily occurs in gene regions encoding the two oligonucleotide-/oligosaccharide-binding (OB) folds and affects key residues required to bind telomeric DNA. POT1-mutated CLL cells have numerous telomeric and chromosomal abnormalities that suggest that POT1 mutations favor the acquisition of the malignant features of CLL cells. The identification of POT1 as a new frequently mutated gene in CLL may facilitate novel approaches for the clinical management of this disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.



  1. 1.

    & Chronic lymphocytic leukemia. N. Engl. J. Med. 333, 1052–1057 (1995).

  2. 2.

    , , , & From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat. Rev. Cancer 10, 37–50 (2010).

  3. 3.

    , & Molecular basis of CLL. Semin. Cancer Biol. 20, 370–376 (2010).

  4. 4.

    & Hematological cancer in 2011: new therapeutic targets and treatment strategies. Nat. Rev. Clin. Oncol. 9, 72–74 (2012).

  5. 5.

    et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475, 101–105 (2011).

  6. 6.

    et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 44, 47–52 (2012).

  7. 7.

    et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J. Exp. Med. 208, 1389–1401 (2011).

  8. 8.

    et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497–2506 (2011).

  9. 9.

    & Pot1, the putative telomere end–binding protein in fission yeast and humans. Science 292, 1171–1175 (2001).

  10. 10.

    & POT1 as a terminal transducer of TRF1 telomere length control. Nature 423, 1013–1018 (2003).

  11. 11.

    & Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am. J. Hum. Genet. 88, 440–449 (2011).

  12. 12.

    et al. TPP1 is required for TERT recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice. Dev. Cell 18, 775–789 (2010).

  13. 13.

    et al. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 23, 2060–2075 (2009).

  14. 14.

    , , , & Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal. Science 327, 1657–1661 (2010).

  15. 15.

    , & Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat. Struct. Mol. Biol. 11, 1223–1229 (2004).

  16. 16.

    et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011).

  17. 17.

    , & POT1 association with TRF2 regulates telomere length. Mol. Cell Biol. 29, 5611–5619 (2009).

  18. 18.

    et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 126, 49–62 (2006).

  19. 19.

    , , , & POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. EMBO J. 24, 2667–2678 (2005).

  20. 20.

    , , & Recent expansion of the telomeric complex in rodents: two distinct POT1 proteins protect mouse telomeres. Cell 126, 63–77 (2006).

  21. 21.

    & Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat. Rev. Cancer 11, 161–176 (2011).

  22. 22.

    et al. Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia. Blood 111, 2246–2252 (2008).

  23. 23.

    et al. Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis. Blood 116, 1899–1907 (2010).

  24. 24.

    et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

  25. 25.

    et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53–58 (2012).

  26. 26.

    et al. Distinct functions of POT1 at telomeres. Mol. Cell Biol. 28, 5251–5264 (2008).

  27. 27.

    et al. International network of cancer genome projects. Nature 464, 993–998 (2010).

  28. 28.

    et al. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 (2007).

  29. 29.

    , , , & Jalview Version 2—a multiple sequence alignment editor and analysis workbench. Bioinformatics 25, 1189–1191 (2009).

  30. 30.

    , & Human Pot1 (protection of telomeres) protein: cytolocalization, gene structure, and alternative splicing. Mol. Cell Biol. 22, 8079–8087 (2002).

  31. 31.

    et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

  32. 32.

    et al. Normal telomere length and chromosomal end capping in poly(ADP-ribose) polymerase–deficient mice and primary cells despite increased chromosomal instability. J. Cell Biol. 154, 49–60 (2001).

  33. 33.

    , , & High-throughput telomere length quantification by FISH and its application to human population studies. Proc. Natl. Acad. Sci. USA 104, 5300–5305 (2007).

Download references


We are grateful to D.A. Puente, S. Guijarro, S. Martín, C. Capdevila, M. Sánchez and L. Plá for excellent technical assistance and to N. Villahoz and C. Muro for excellent work in the coordination of the CLL Spanish Consortium. We thank T. de Lange (The Rockefeller University) for providing the POT1 plasmid. We are also very grateful to all individuals with CLL who have participated in this study. This work was funded by the Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (ISCIII) and the Red Temática de Investigación del Cáncer (RTICC) del ISCIII. C.L.-O. is an Investigator of the Botín Foundation. Research in the laboratory of M.A.B. is funded by the Spanish Ministry of Economy and Competitiveness Projects SAF2008-05384 and CSD2007-00017, the Madrid Regional Government Project S2010/BMD-2303 (ReCaRe), the European Union Seventh Framework Programme Project FHEALTH-2010-259749 (EuroBATS), The European Research Council (ERC) Project GA 232854 (TEL STEM CELL), the Körber European Science Award from the Körber Foundation, the Preclinical Research Award from Fundación Lilly (Spain), Fundación Botín (Spain) and the AXA Research Fund.

Author information

Author notes

    • Andrew J Ramsay
    • , Víctor Quesada
    •  & Miguel Foronda

    These authors contributed equally to this work.


  1. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain.

    • Andrew J Ramsay
    • , Víctor Quesada
    • , David Rodríguez
    • , Agnieszka Kwarciak
    • , Cecilia Garabaya
    • , Xose S Puente
    •  & Carlos López-Otín
  2. Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

    • Miguel Foronda
    • , Mercedes Gallardo
    •  & María A Blasco
  3. Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

    • Laura Conde
    • , Alejandra Martínez-Trillos
    • , Neus Villamor
    • , Mónica López-Guerra
    • , Armando López-Guillermo
    •  & Elías Campo


  1. Search for Andrew J Ramsay in:

  2. Search for Víctor Quesada in:

  3. Search for Miguel Foronda in:

  4. Search for Laura Conde in:

  5. Search for Alejandra Martínez-Trillos in:

  6. Search for Neus Villamor in:

  7. Search for David Rodríguez in:

  8. Search for Agnieszka Kwarciak in:

  9. Search for Cecilia Garabaya in:

  10. Search for Mercedes Gallardo in:

  11. Search for Mónica López-Guerra in:

  12. Search for Armando López-Guillermo in:

  13. Search for Xose S Puente in:

  14. Search for María A Blasco in:

  15. Search for Elías Campo in:

  16. Search for Carlos López-Otín in:


V.Q., A.J.R., A.K. and X.S.P. developed the bioinformatics algorithms and performed the analysis of sequence data. A.J.R., M.F., D.R., C.G. and M.G. performed functional studies. L.C., A.M.-T., N.V., M.L.-G. and A.L.-G. performed clinical analysis. A.J.R., V.Q., M.A.B., E.C. and C.L.-O. conceived and directed the research and wrote the manuscript, which all authors have approved.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to María A Blasco or Elías Campo or Carlos López-Otín.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–6 and Supplementary Figures 1–4

About this article

Publication history






Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing