Article

Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease

  • Nature Communications 3, Article number: 623 (2012)
  • doi:10.1038/ncomms1623
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Abstract

Recent evidence shows increased and decreased expression of Ezh2 in cancer, suggesting a dual role as an oncogene or tumour suppressor. To investigate the mechanism by which Ezh2-mediated H3K27 methylation leads to cancer, we generated conditional Ezh2 knock-in (Ezh2-KI) mice. Here we show that induced Ezh2 haematopoietic expression increases the number and proliferation of repopulating haematopoietic stem cells. Ezh2-KI mice develop myeloproliferative disorder, featuring excessive myeloid expansion in bone marrow and spleen, leukocytosis and splenomegaly. Competitive and serial transplantations demonstrate progressive myeloid commitment of Ezh2-KI haematopoietic stem cells. Transplanted self-renewing haematopoietic stem cells from Ezh2-KI mice induce myeloproliferative disorder, suggesting that the Ezh2 gain-of-function arises in the haematopoietic stem cell pool, and not at later stages of myelopoiesis. At the molecular level, Ezh2 regulates haematopoietic stem cell-specific genes such as Evi-1 and Ntrk3, aberrantly found in haematologic malignancies. These results demonstrate a stem cell-specific Ezh2 oncogenic role in myeloid disorders, and suggest possible therapeutic applications in Ezh2-related haematological malignancies.

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Change history

  • Updated online 07 March 2017

    This paper has been retracted at the request of the authors.

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Acknowledgements

We are grateful to Giovanna Giovinazzo, Luis-Miguel Criado, Maria Montoya and their teams (CNIC) for technical support. We also thank Simon Bartlett (CNIC) for English editing, Dr Serrano for helpful discussion, and Purificacion Arribas for her wonderful technical assistance. S. Gonzalez is funded by the Human Frontiers Science Program Organization, the Spanish Ministries of Science and Innovation (SAF2010-15386) and Health (FIS PI06/0627) The CNIC is supported by the Ministry of Science and Innovation and the Pro-CNIC Foundation.

Author information

Affiliations

  1. Stem Cell Aging Group, Spanish National Cardiovascular Research Center (CNIC), E-28029 Madrid, Spain.

    • A. Herrera-Merchan
    • , L. Arranz
    •  & S. Gonzalez
  2. Cellomic Unit, Spanish National Cardiovascular Research Center (CNIC), E-28029 Madrid, Spain.

    • J.M. Ligos
  3. Animal Unit, Spanish National Cardiovascular Research Center (CNIC), E-28029 Madrid, Spain.

    • A. de Molina
  4. Genomics Unit, Spanish National Cancer Research Center (CNIO), E-28029 Madrid, Spain.

    • O. Dominguez

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Contributions

A.H-M. performed most of the experiments, contributed to data analysis, and discussion of the paper. L.A. helps with technical issues regarding gene expression assays. J.M.L. supervised the cytometric analyses. A.M. performed all pathological analyses. O.D. designed and supervised the gene expression data. S.G. designed and supervised the study, secured funding, analysed the data and wrote the paper. All authors discussed the results and commented on the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to S. Gonzalez.

Supplementary information

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    Supplementary Information

    Supplementary Figures S1-S14, Supplementary Tables S1-S3, Supplementary Methods and Supplementary References

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