title: Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles.
abstract: Chronic lymphocytic leukemia (CLL) can be divided into prognostic subgroups based on the IGHV gene mutational status, and is further characterized by multiple subsets of cases with quasi-identical or stereotyped B cell receptors that also share clinical and biological features. We recently reported differential DNA methylation profiles in IGHV-mutated and IGHV-unmutated CLL subgroups. For the first time, we here explore the global methylation profiles of stereotyped subsets with different prognosis, by applying high-resolution methylation arrays on CLL samples from three major stereotyped subsets: the poor-prognostic subsets #1 (n = 15) and #2 (n = 9) and the favorable-prognostic subset #4 (n = 15). Overall, the three subsets exhibited significantly different methylation profiles, which only partially overlapped with those observed in our previous study according to IGHV gene mutational status. Specifically, gene ontology analysis of the differentially methylated genes revealed a clear enrichment of genes involved in immune response, such as B cell activation (e.g., CD80, CD86 and IL10), with higher methylation levels in subset #1 than subsets #2 and #4. Accordingly, higher expression of the co-stimulatory molecules CD80 and CD86 was demonstrated in subset #4 vs. subset #1, pointing to a key role for these molecules in the crosstalk of CLL subset #4 cells with the microenvironment. In summary, investigation of three prototypic, stereotyped CLL subsets revealed distinct DNA methylation profiles for each subset, which suggests subset-biased patterns of transcriptional control and highlights a key role for epigenetics during leukemogenesis.
authors.affiliation: Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Meena
authors.initials: M
authors.lastname: Kanduri
authors.forename: Millaray
authors.initials: M
authors.lastname: Marincevic
authors.forename: Anna M
authors.initials: AM
authors.lastname: Halldórsdóttir
authors.forename: Larry
authors.initials: L
authors.lastname: Mansouri
authors.forename: Katarina
authors.initials: K
authors.lastname: Junevik
authors.forename: Stavroula
authors.initials: S
authors.lastname: Ntoufa
authors.forename: Hanna Göransson
authors.initials: HG
authors.lastname: Kultima
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Andersson
authors.forename: Hans
authors.initials: H
authors.lastname: Ehrencrona
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D011379:Prognosis; D014158:Transcription, Genetic
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D007143:Immunoglobulin Heavy Chains