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Background  The sensitivity of chronic lymphocytic leukemia (CLL) cells to current treatments, both  in vitro  and  in vivo , relies on their ability to activate apoptotic death. CLL cells resistant to DNA damage-induced apoptosis display deregulation of a specific set of genes.    Methods  Microarray hybridization (Human GeneChip, Affymetrix), immunofluorescent  in situ  labeling coupled with video-microscopy recording/analyses, chromatin-immunoprecipitation (ChIP), polymerase chain reactions (PCR), real-time quantitative PCR (RT-QPCR) and bisulfite genome sequencing were the main methods applied. Statistical analyses were performed by applying GCRMA and SAM analysis (microarray data) and Student's t-test or Mann & Whitney's U-test.    Results  Herein we show that, remarkably, in a resistant male CLL cells the vast majority of genes were down-regulated compared with sensitive cells, whereas this was not the case in cells derived from females. This gene down-regulation was found to be associated with an overall gain of heterochromatin as evidenced by immunofluorescent labeling of heterochromatin protein 1α (HP-1), trimethylated histone 3 lysine 9 (3metH3K9), and 5-methylcytidine (5metC). Notably, 17 genes were found to be commonly deregulated in resistant male and female cell samples. Among these,  RELB  was identified as a discriminatory candidate gene repressed in the male and upregulated in the female resistant cells.    Conclusion  The molecular defects in the silencing of  RELB  involve an increase in H3K9- but not CpG-island methylation in the promoter regions. Increase in acetyl-H3 in resistant female but not male CLL samples as well as a decrease of total cellular level of RelB after an inhibition of histone deacetylase (HDAC) by trichostatin A (TSA), further emphasize the role of epigenetic modifications which could discriminate two CLL subsets. Together, these results highlighted the epigenetic  RELB  silencing as a new marker of the progressive disease in males.

bmc medical genomics

Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELBin an aggressive subset of chronic lymphocytic leukemia in males