Cross‐talk between <scp>DNA</scp> methylation and active histone modifications regulates aberrant expression of <scp>ZAP</scp>70 in <scp>CLL</scp>

Abstract

Abstract Zeta‐associated protein of 70 kD ( ZAP 70) is a recognized adverse prognostic marker in chronic lymphocytic leukaemia ( CLL ) associated with enhanced B ‐cell receptor signalling, significantly more aggressive disease course and poor overall survival. Zeta‐associated protein of 70 kD is ordinarily expressed in T cells where it has a crucial role in T ‐cell receptor signalling, whereas its aberrant expression in CLL leads to enhanced B ‐cell receptor signalling and significantly more aggressive disease course. Although much is known about the activation of ZAP 70 following engagement of T ‐cell receptor, there are little data on the regulation of ZAP 70 gene expression in normal T cells or CLL . To understand the molecular events underpinning epigenetic regulation of ZAP 70 gene in CLL , we have defined ZAP 70 promoter region and outlined the regions crucial in regulating the gene activity. Following a direct comparison of ZAP 70+ and ZAP 70− primary CLLs , we show ZAP 70 promoter in expressing CLLs to be associated with a spectrum of active histone modifications, some of which are tightly linked to aberrant DNA methylation in CLL . Cross‐talk between histone modifications and reduced DNA methylation culminates in transcriptional de‐repression of ZAP 70 . Moreover, treatment with histone deacetylase ( HDAC ) and DNA methylation inhibitors results in recovery of ZAP 70 expression, which provides a possible explanation for the failure of HDAC inhibitors in CLL treatment and might serve as a cautionary warning for their future use in treatment of this leukaemia.