Abstract

Aging is characterized by clonal expansion of myeloid-biased hematopoietic stem cells and by increased risk of myeloid malignancies. Exome sequencing of three elderly females with clonal hematopoiesis, demonstrated by X-inactivation analysis, identified somatic TET2 mutations. Recurrence testing identified TET2 mutations in 10 out of 182 individuals with X-inactivation skewing. TET2 mutations were specific to individuals with clonal hematopoiesis without hematological malignancies and were associated with alterations in DNA methylation.

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Acknowledgements

We thank members of the Levine and Busque laboratories for helpful comments and discussion. This work was supported by a grant from the National Cancer Institute Physical Sciences Oncology Center (U54CA143798-01) to R.L.L. and A.M., by grant 1R01CA138234-01 to R.L.L. and by grants 1R01CA129831 and 1R01CA129831-03S1 to L.A.G. from the National Cancer Institute. A. Vasanthakumar is supported by a US National Institutes of Health F32 award. M.E.F. is supported by a Leukemia and Lymphoma Society Special Fellow award and a Doris Duke Charitable Foundation Clinical Scientist Development Award. O.A.-W. is an American Society of Hematology Basic Research Fellow. A.M. is a Burroughs Wellcome Clinical Translational Scholar and is also supported by the Sackler Center for Biomedical and Physical Sciences. R.L.L. is an Early Career Award Recipient of the Howard Hughes Medical Institute. R.L.L. and A.M. are funded by Leukemia and Lymphoma Society Scholar Awards. All subjects answered a medical questionnaire and gave informed consent. The study was approved by the Maisonneuve-Rosemont Hospital's Ethics Committee in 1998 and is reapproved yearly in accordance with institutional bylaws.

Author information

Author notes

    • Lambert Busque
    •  & Jay P Patel

    These authors contributed equally to this work.

    • Omar Abdel-Wahab
    •  & Ross L Levine

    These authors jointly directed this work.

Affiliations

  1. Research Centre, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.

    • Lambert Busque
    •  & Luigina Mollica
  2. Department of Hematology, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.

    • Lambert Busque
    • , Zineb Hamilou
    •  & Luigina Mollica
  3. University of Montreal, Montreal, Quebec, Canada.

    • Lambert Busque
    • , Zineb Hamilou
    •  & Luigina Mollica
  4. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Jay P Patel
    • , Adriana Heguy
    • , Parva K Bhatt
    • , Cameron W Brennan
    • , Omar Abdel-Wahab
    •  & Ross L Levine
  5. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

    • Maria E Figueroa
  6. Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.

    • Aparna Vasanthakumar
    •  & Lucy A Godley
  7. Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada.

    • Sylvie Provost
  8. Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Juan Li
    •  & Agnes Viale
  9. Bioinformatics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Maryam Hassimi
    •  & Nicholas Socci
  10. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Mithat Gonen
  11. Department of Physiology and Biophysics and the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York, USA.

    • Christopher E Mason
  12. Graduate School of Biomedical Sciences, Weill Medical College of Cornell University, New York, New York, USA.

    • Christopher E Mason
    • , Ari Melnick
    •  & Ross L Levine
  13. Division of Hematology/Oncology, Weill Medical College of Cornell University, New York, New York, USA.

    • Ari Melnick
  14. Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Cameron W Brennan
  15. Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Omar Abdel-Wahab
    •  & Ross L Levine

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Contributions

L.B., J.P.P., O.A.-W. and R.L.L. designed the study. L.B., S.P., Z.H. and L.M. collected samples and provided genetic and clinical annotation. J.P.P., J.L., A. Vasanthakumar, A.H., M.H., N.S., P.K.B., C.E.M. and C.W.B. performed sequence analysis and validated mutations. M.E.F., A. Viale, A.M. and L.A.G. performed methylation analysis. M.G. performed statistical analysis. L.B., J.P.P., O.A.-W. and R.L.L. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lambert Busque or Ross L Levine.

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DOI

https://doi.org/10.1038/ng.2413

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