Research Papers:

Alterations in DNA methylation/demethylation intermediates predict clinical outcome in chronic lymphocytic leukemia

Cristina Bagacean, Adrian Tempescul, Christelle Le Dantec, Anne Bordron, Audrey Mohr, Hussam Saad, Valerie Olivier, Mihnea Zdrenghea, Victor Cristea, Pierre-François Cartron, Nathalie Douet-Guilbert, Christian Berthou and Yves Renaudineau _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2017; 8:65699-65716. https://doi.org/10.18632/oncotarget.20081

Metrics: PDF 1861 views  |   HTML 3207 views  |   ?  


Cristina Bagacean1,2,3, Adrian Tempescul1,4, Christelle Le Dantec1, Anne Bordron1, Audrey Mohr1, Hussam Saad4, Valerie Olivier2, Mihnea Zdrenghea3,5, Victor Cristea3, Pierre-François Cartron6, Nathalie Douet-Guilbert7, Christian Berthou1,4 and Yves Renaudineau1,2

1U1227 B Lymphocytes and Autoimmunity, University of Brest, INSERM, IBSAM, Labex IGO, Networks IC-CGO and REpiCGO from Cancéropôle Grand Ouest, Brest, France

2Laboratory of Immunology and Immunotherapy, Brest University Medical School Hospital, Brest, France

3Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

4Department of Hematology, Brest University Medical School Hospital, Brest, France

5Department of Hematology, ‘Ion Chiricuta’ Oncology Institute, Cluj-Napoca, Romania

6Inserm, U892, Epigenetics Network from Cancéropôle Grand Ouest, Nantes, France

7Laboratory of Cytogenetics, Brest University Medical School Hospital, Brest, France

Correspondence to:

Yves Renaudineau, email: [email protected]

Keywords: chronic lymphocytic leukemia, methylation, hydroxymethylation, TET, SAT1

Received: June 08, 2017     Accepted: July 26, 2017     Published: August 09, 2017


Cytosine derivative dysregulations represent important epigenetic modifications whose impact on the clinical outcome in chronic lymphocytic leukemia (CLL) is incompletely understood. Hence, global levels of 5-methylcytosine (5-mCyt), 5-hydroxymethylcytosine (5-hmCyt), 5-carboxylcytosine (5-CaCyt) and 5-hydroxymethyluracil were tested in purified B cells from CLL patients (n = 55) and controls (n = 17). The DNA methylation ‘writers’ (DNA methyltransferases [DNMT1/3A/3B]), ‘readers’ (methyl-CpG-binding domain [MBD2/4]), ‘editors’ (ten-eleven translocation [TET1/2/3]) and ‘modulators’ (SAT1) were also evaluated. Accordingly, patients were stratified into three subgroups. First, a subgroup with a global deficit in cytosine derivatives characterized by hyperlymphocytosis, reduced median progression free survival (PFS = 52 months) and shorter treatment free survival (TFS = 112 months) was identified. In this subgroup, major epigenetic modifications were highlighted including a reduction of 5-mCyt, 5-hmCyt, 5-CaCyt associated with DNMT3A, MBD2/4 and TET1/2 downregulation. Second, the cytosine derivative analysis revealed a subgroup with a partial deficit (PFS = 84, TFS = 120 months), mainly affecting DNA demethylation (5-hmCyt reduction, SAT1 induction). Third, a subgroup epigenetically similar to controls was identified (PFS and TFS > 120 months). The prognostic impact of stratifying CLL patients within three epigenetic subgroups was confirmed in a validation cohort. In conclusion, our results suggest that dysregulations of cytosine derivative regulators represent major events acquired during CLL progression and are independent from IGHV mutational status.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 20081