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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Meena Kanduri
  • Millaray Marincevic
  • Anna M. Halldorsdottir
  • Larry Mansouri
  • Katarina Junevik
  • Stavroula Ntoufa
  • Hanna Goransson Kultima
  • Anders Isaksson
  • Gunnar Juliusson
  • Per-Ola Andersson
  • Hans Ehrencrona
  • Kostas Stamatopoulos
  • Richard Rosenquist
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

Keywords

  • Chronic lymphocytic leukemia, DNA methylation, microarrays, stereotyped, B cell receptors, immune response
Original languageEnglish
Pages (from-to)1435-1442
JournalEpigenetics
Volume7
Issue number12
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes