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Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles

Kanduri, Meena; Marincevic, Millaray; Halldorsdottir, Anna M.; Mansouri, Larry; Junevik, Katarina; Ntoufa, Stavroula; Kultima, Hanna Goransson; Isaksson, Anders; Juliusson, Gunnar LU and Andersson, Per-Ola, et al. (2012) In Epigenetics 7(12). p.1435-1442
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... (More)
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. (Less)
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keywords
Chronic lymphocytic leukemia, DNA methylation, microarrays, stereotyped, B cell receptors, immune response
in
Epigenetics
volume
7
issue
12
pages
1435 - 1442
publisher
Landes Bioscience
external identifiers
  • wos:000311938500010
  • scopus:84870735334
ISSN
1559-2294
DOI
10.4161/epi.22901
language
English
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yes
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d2095fc7-153a-4737-83ab-d8c7064c2217 (old id 3372412)
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2013-02-01 06:59:23
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2017-10-22 03:28:50
@article{d2095fc7-153a-4737-83ab-d8c7064c2217,
  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.},
  author       = {Kanduri, Meena and Marincevic, Millaray and Halldorsdottir, Anna M. and Mansouri, Larry and Junevik, Katarina and Ntoufa, Stavroula and Kultima, Hanna Goransson and Isaksson, Anders and Juliusson, Gunnar and Andersson, Per-Ola and Ehrencrona, Hans and Stamatopoulos, Kostas and Rosenquist, Richard},
  issn         = {1559-2294},
  keyword      = {Chronic lymphocytic leukemia,DNA methylation,microarrays,stereotyped,B cell receptors,immune response},
  language     = {eng},
  number       = {12},
  pages        = {1435--1442},
  publisher    = {Landes Bioscience},
  series       = {Epigenetics},
  title        = {Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles},
  url          = {http://dx.doi.org/10.4161/epi.22901},
  volume       = {7},
  year         = {2012},
}