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Natural killer ( NK) large granular lymphocyte ( LGL) leukaemia features a clonal proliferation of CD3− NK cells that can be classified into either aggressive or chronic categories. The NKL cell line, derived from an aggressive Asian NK cell leukaemia, and patient samples from chronic NK- LGL leukaemia were used in our study to probe for synergistic efficacy of the epigenetic drugs vorinostat ( SAHA) and cladribine in this disease. We demonstrate that histone deacetylases ( HDACs) are over-expressed in both aggressive and chronic NK leukaemia. Administration of the HDAC inhibitor SAHA reduces class I and II HDAC expression and enhances histone acetylation in leukaemic NK cells. In vitro combination treatment with SAHA and cladribine dose-dependently exerts synergistic cytotoxic and apoptotic effects on leukaemic NK cells. Expression profiling of apoptotic regulatory genes suggests that both compounds led to caspase-dependent apoptosis through activation of intrinsic mitochondrial and extrinsic death receptor pathways. Collectively, these data show that combined epigenetic therapy, using HDAC and DNA methyltransferase inhibitors, may be a promising therapeutic approach for NK- LGL leukaemia. [ABSTRACT FROM AUTHOR]