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

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.

[1]  T. Shanafelt,et al.  Chronic lymphocytic leukaemia , 2018, The Lancet.

[2]  Salvatore F. E. Oliviero,et al.  Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22 , 2017, Leukemia.

[3]  Huanming Yang,et al.  Evolution of multiple cell clones over a 29-year period of a CLL patient , 2016, Nature Communications.

[4]  L. Lagneaux,et al.  Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance , 2016, Clinical Epigenetics.

[5]  Lynette M. Smith,et al.  Loss of Dnmt3a induces CLL and PTCL with distinct methylomes and transcriptomes in mice , 2016, Scientific Reports.

[6]  R. Opavsky,et al.  Aberrant Promoter Hypomethylation in CLL: Does It Matter for Disease Development? , 2016, Front. Oncol..

[7]  D. Isenberg,et al.  CD5 expression promotes IL-10 production through activation of the MAPK/Erk pathway and upregulation of TRPC1 channels in B lymphocytes , 2016, Cellular & Molecular Immunology.

[8]  Renata Walewska,et al.  Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks , 2016, Nature Communications.

[9]  Wei Li,et al.  DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells , 2016, Nature Genetics.

[10]  Lirong Pei,et al.  Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming , 2016, Oncotarget.

[11]  S. Costinean,et al.  Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a. , 2016, Cell reports.

[12]  V. Cristea,et al.  Anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia: from uncertainties to promises. , 2016, Immunotherapy.

[13]  J. Byrd,et al.  DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia , 2016, Nature Genetics.

[14]  R. Jaenisch,et al.  Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation , 2015, Molecular and Cellular Biology.

[15]  Zhaohui S. Qin,et al.  Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice. , 2015, Cell reports.

[16]  G. Raca,et al.  Predicting Prognosis in Chronic Lymphocytic Leukemia in the Contemporary Era. , 2015, JAMA oncology.

[17]  G. Raca,et al.  Prognosis in Chronic Lymphocytic Leukemia-Reply. , 2015, JAMA oncology.

[18]  Ronald P. Schuyler,et al.  Whole-genome fingerprint of the DNA methylome during human B cell differentiation , 2015, Nature Genetics.

[19]  B. Ebert,et al.  Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms. , 2015, Blood.

[20]  Michael J. Ziller,et al.  Locally disordered methylation forms the basis of intratumor methylome variation in chronic lymphocytic leukemia. , 2014, Cancer cell.

[21]  J. Gribben,et al.  Loss of 5-hydroxymethylcytosine in cancer: cause or consequence? , 2014, Genomics.

[22]  E. Giné,et al.  A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact , 2014, Leukemia.

[23]  Emanuela M. Ghia,et al.  MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. , 2014, Blood.

[24]  V. Bollati,et al.  Relevance of telomere/telomerase system impairment in early stage chronic lymphocytic leukemia , 2014, Genes, chromosomes & cancer.

[25]  R. Gay,et al.  Inhibition of Spermidine/Spermine N1‐Acetyltransferase Activity: A New Therapeutic Concept in Rheumatoid Arthritis , 2014, Arthritis & rheumatology.

[26]  B. Espinet,et al.  Genetic Abnormalities in Chronic Lymphocytic Leukemia: Where We Are and Where We Go , 2014, BioMed research international.

[27]  R. Jaenisch,et al.  Tumor suppressor functions of Dnmt3a and Dnmt3b in the prevention of malignant mouse lymphopoiesis , 2014, Leukemia.

[28]  Christopher R. Schmidt,et al.  Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia. , 2014, Cancer discovery.

[29]  Marcos González,et al.  TET2 Overexpression in Chronic Lymphocytic Leukemia Is Unrelated to the Presence of TET2 Variations , 2014, BioMed research international.

[30]  Alfonso Valencia,et al.  Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia , 2014, Genome research.

[31]  J. Pers,et al.  Epigenetic dysregulation in salivary glands from patients with primary Sjögren's syndrome may be ascribed to infiltrating B cells. , 2013, Journal of autoimmunity.

[32]  M. Shirakawa,et al.  Structural Basis of the Versatile DNA Recognition Ability of the Methyl-CpG Binding Domain of Methyl-CpG Binding Domain Protein 4* , 2013, The Journal of Biological Chemistry.

[33]  Alfonso Valencia,et al.  Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia , 2012, Nature Genetics.

[34]  Huijue Jia,et al.  AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation , 2012, Nature chemical biology.

[35]  Gerald L. Arthur,et al.  Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia , 2012, Epigenetics.

[36]  R. Gay,et al.  Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. , 2012, Arthritis and rheumatism.

[37]  Michael A. Freitas,et al.  Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL) , 2012, Proceedings of the National Academy of Sciences.

[38]  T. Ideker,et al.  Subnetwork-based analysis of chronic lymphocytic leukemia identifies pathways that associate with disease progression. , 2011, Blood.

[39]  J. Pers,et al.  CD5 Promotes IL-10 Production in Chronic Lymphocytic Leukemia B Cells through STAT3 and NFAT2 Activation , 2011, The Journal of Immunology.

[40]  A. Baccarelli,et al.  Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia , 2011, Epigenetics.

[41]  Hanna Göransson,et al.  Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia. , 2010, Blood.

[42]  J. Byrd,et al.  Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia , 2009, Proceedings of the National Academy of Sciences.

[43]  David R. Liu,et al.  Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1 , 2009, Science.

[44]  N. Shinton WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues , 2007 .

[45]  L. Marton,et al.  Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases , 2007, Nature Reviews Drug Discovery.

[46]  S. Hillion,et al.  An alternative exon 1 of the CD5 gene regulates CD5 expression in human B lymphocytes. , 2005, Blood.

[47]  A. El-Osta,et al.  Expression analysis of the epigenetic methyltransferases and Methyl-CpG binding protein families in the normal B-cell and B-cell chronic lymphocytic leukemia (CLL) , 2004, Cancer biology & therapy.

[48]  M Hummel,et al.  Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936 , 2003, Leukemia.

[49]  Y. Tu,et al.  Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells , 2001, The Journal of experimental medicine.

[50]  E. Scott,et al.  Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. , 1994, Science.

[51]  M. Hallek,et al.  Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[52]  Trevor J Pugh,et al.  Mutational heterogeneity in cancer and the search for new cancer genes , 2014 .

[53]  A. Isaksson,et al.  450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments , 2013, Leukemia.

[54]  V. Giudicelli,et al.  IMGT(®) tools for the nucleotide analysis of immunoglobulin (IG) and T cell receptor (TR) V-(D)-J repertoires, polymorphisms, and IG mutations: IMGT/V-QUEST and IMGT/HighV-QUEST for NGS. , 2012, Methods in molecular biology.

[55]  P. Schär,et al.  Communicated by: E. Nigg , 2022 .