Alterations in DNA methylation/demethylation intermediates predict clinical outcome in chronic lymphocytic leukemia
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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
Yves Renaudineau, email: firstname.lastname@example.org
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.
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