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Spotlight on Epigenetics in Hematologic Malignancies

The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases

Leukemia volume 28, pages 485–496 (2014)Cite this article

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Abstract

Ten-Eleven Translocation-2 (TET2) inactivation through loss-of-function mutation, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutation is a common event in myeloid and lymphoid malignancies. TET2 gene mutations similar to those observed in myeloid and lymphoid malignancies also accumulate with age in otherwise healthy subjects with clonal hematopoiesis. TET2 is one of the three proteins of the TET (Ten-Eleven Translocation) family, which are evolutionarily conserved dioxygenases that catalyze the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promote DNA demethylation. TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which is enhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in the hematopoietic tissue, especially in hematopoietic stem cells. In addition to their hydroxylase activity, TET proteins recruit the O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) enzyme to chromatin, which promotes post-transcriptional modifications of histones and facilitates gene expression. The TET2 level is regulated by interaction with IDAX, originating from TET2 gene fission during evolution, and by the microRNA miR-22. TET2 has pleiotropic roles during hematopoiesis, including stem-cell self-renewal, lineage commitment and terminal differentiation of monocytes. Analysis of Tet2 knockout mice, which are viable and fertile, demonstrated that Tet2 functions as a tumor suppressor whose haploinsufficiency initiates myeloid and lymphoid transformations. This review summarizes the recently identified TET2 physiological and pathological functions and discusses how this knowledge influences our therapeutic approaches in hematological malignancies and possibly other tumor types.

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Acknowledgements

ES, OAB and WV are heading teams independently supported by the Ligue Nationale Contre le Cancer (Equipes labellisées) and receive grants from Inserm, Agence National de la Recherche and Institut National du Cancer. We are grateful to all members of Inserm UMR895 and UMR1009 who were involved in cited works or provided helpful comments. We apologize to all colleagues whose work was not cited because of space restrictions.

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Authors and Affiliations

  1. Hematology Department, Gustave Roussy, Villejuif, France

    E Solary, O A Bernard & W Vainchenker

  2. Inserm UMR1009, Gustave Roussy, Villejuif cedex, France

    E Solary & W Vainchenker

  3. Faculty of Medicine, University Paris-Sud, Le Kremlin-Bicêtre, France

    E Solary, O A Bernard & W Vainchenker

  4. Inserm UMR985, Gustave Roussy, Villejuif, France

    O A Bernard

  5. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    A Tefferi

  6. Faculty of Medicine, Laboratory of Cancer Epigenetics, Université Libre de Bruxelles, Brussels, Belgium

    F Fuks

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  1. E Solary
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  3. A Tefferi
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Correspondence to E Solary.

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Solary, E., Bernard, O., Tefferi, A. et al. The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia 28, 485–496 (2014). https://doi.org/10.1038/leu.2013.337

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  • DOI: https://doi.org/10.1038/leu.2013.337

Keywords

  • TET2
  • epigenetics
  • DNA methylation
  • dioxygenase
  • stem cell
  • differentiation

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