Research Papers:

Adult T cell leukemia aggressivenness correlates with loss of both 5-hydroxymethylcytosine and TET2 expression

Ambroise Marçais, Laetitia Waast, Julie Bruneau, Katia Hanssens, Vahid Asnafi, Philippe Gaulard, Felipe Suarez, Patrice Dubreuil, Antoine Gessain, Olivier Hermine and Claudine Pique _

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Oncotarget. 2017; 8:52256-52268. https://doi.org/10.18632/oncotarget.13665

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Ambroise Marçais1,2, Laetitia Waast2, Julie Bruneau3,9, Katia Hanssens4, Vahid Asnafi5, Philippe Gaulard6,7, Felipe Suarez1, Patrice Dubreuil4, Antoine Gessain8, Olivier Hermine1,9,* and Claudine Pique2,*

1Service d’Hématologie, Hôpital Universitaire Necker-Enfants Malades, APHP, Université Paris Descartes, Institut Imagine, INSERM U1163-CNRS ERL8254, Sorbonne Paris Cité, Paris, France

2INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Institut Cochin, Paris, France

3Département de Pathologie, Hôpital Universitaire Necker-Enfants Malades, APHP, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

4INSERM U1068, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Université de la Méditerranée, Marseille, France

5Institut Necker-Enfants Malades (INEM), INSERM U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker, Paris, France

6Département de Pathologie, Hôpital Henri Mondor, APHP, Créteil, France

7INSERM U955, Créteil, France Université Paris Est, Créteil, France

8Unité d’Épidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, CNRS, UMR 3569, Institut Pasteur, Paris, France

9Imagine Institute, INSERM UMR 1163 and CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hemathological Disorders and Therapeutic Implication, Hôpital Necker, Paris, France

*These authors contributed equally to this work

Correspondence to:

Ambroise Marçais, email: [email protected]

Olivier Hermine, email: [email protected]

Claudine Pique, email: [email protected]

Keywords: retrovirus, T-cells, leukemia, DNA hydroxymethylation, ten eleven translocation

Received: August 02, 2016     Accepted: November 21, 2016     Published: November 26, 2016


Mutations in TET2, encoding one of the TET members responsible for the conversion of DNA cytosine methylation to hydroxymethylation (5-hmc), have been recently described in Human T-lymphotropic virus type 1-associated adult T-cell leukemia/lymphoma (ATLL). However, neither the amount of genomic 5-hmc in ATLL tumor cells nor TET2 expression has been studied yet. In this study, we analyzed these two parameters as well as the mutational status of TET2 in ATLL patients. By employing a direct in situ approach, we documented that tumor T cells infiltrating lymph nodes exhibit low level of 5-hmc compared to residual normal T cells. Furthermore, this 5-hmc defect was more pronounced in tumor T cells from acute patients than from chronic ones and correlated with reduced expression of TET2 protein. TET2 variations were found in 14 patients (20%), including 13 with aggressive forms. Strikingly, 9 of the 14 patients showed the same variation (SNP rs72963007), whose frequency in ATLL patients was significantly higher than that of an ethnically matched control population (13% vs. 5%). However, no reduction of 5-hmc was found in PBMC from individuals possessing the variant rs72963007 TET2 allele, as compared to wild-type individuals. In contrast, a robust correlation was observed between 5-hmc and the levels of TET2 mRNA. Finally, loss of 5-hmc and TET2 downregulation both correlated with poor survival. These findings demonstrate that ATLL progression coincides with loss of genomic 5-hmc and indicate that downregulation of TET2, rather than TET2 mutations, is the key mechanism involved in 5-hmc modulation during ATLL progression.

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