Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of promoter and undetectable expression of gene.

Genome methylation profiles define naïve-like (n-CLL), memory-like (m-CLL), and intermediate (i-CLL) subsets of chronic lymphocytic leukaemia (CLL). The profiles can be easily determined by the analysis of the five-CpG signature. m-CLL, i-CLL, and n-CLL with the good, intermediate, and poor prognoses, respectively, differ by the somatic hypermutation status of the immunoglobulin heavy chain variable gene (IGHV), a widely used prognostic predictor in CLL. We have previously shown that the expression of , encoding a ROR1 ligand, distinguishes patients with the worse outcome within the prognostically favourable IGHV-mutated subgroup. To analyse the mechanisms controlling expression, we investigated the methylation status of 54 CpG sites within the promoter and its relation to the gene expression. In a cohort of 59 CLL patients balanced for combinations of IGHV and statuses, we identified three promoter CpG sites whose methylation level correlated with the expression within the IGHV-mutated subgroup. Further, we complemented our data with the methylation status of the five-CpG signature. IGHV-mutated/-negative and IGHV-mutated/-positive cases overlapped with m‑CLL and i‑CLL methylation subgroups, respectively, while most IGHV‑unmutated samples were assigned to n-CLL. Median methylation levels of all the three CpG sites in the promoter were lowest in i-CLL. Finally, a detailed analysis of m-CLL and i-CLL showed that undetectable expression predicts longer treatment-free survival with higher statistical significance than the classification according to the five-CpG signature. To conclude, a favourable m-CLL subgroup is associated with mutated IGHV and undetectable expression due to its promoter methylation.