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POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia

Abstract

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.

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Figure 1: Structural impact of POT1 somatic mutations.
Figure 2: Biological properties of wild-type POT1 and the Tyr36Asn and Tyr223Cys POT1 mutants.
Figure 3: Chromosomal aberrations in cells from individuals with CLL expressing mutated POT1.

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Acknowledgements

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.

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Authors

Contributions

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.

Corresponding authors

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

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The authors declare no competing financial interests.

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Supplementary Tables 1–6 and Supplementary Figures 1–4 (PDF 4171 kb)

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Ramsay, A., Quesada, V., Foronda, M. et al. POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nat Genet 45, 526–530 (2013). https://doi.org/10.1038/ng.2584

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