Alterations in DNA methylation/demethylation intermediates predict clinical outcome in chronic lymphocytic leukemia
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
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.