Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia

Xiaoshen Sun, Zainul S. Hasanali, Allshine Chen, Dianzheng Zhang, Xin Liu, Hong-Gang Wang, David J. Feith, Thomas P. Loughran, Kailin Xu

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)371-383
Number of pages13
JournalBritish Journal of Haematology
Volume168
Issue number3
DOIs
StatePublished - Feb 1 2015

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Large Granular Lymphocytic Leukemia
Cladribine
Histone Deacetylases
Apoptosis
Natural Killer Cells
Epigenomics
Death Domain Receptors
Methyltransferases
Regulator Genes
Acetylation
Caspases
Histones
Leukemia
Therapeutics
vorinostat
Cell Line
DNA
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Sun, Xiaoshen ; Hasanali, Zainul S. ; Chen, Allshine ; Zhang, Dianzheng ; Liu, Xin ; Wang, Hong-Gang ; Feith, David J. ; Loughran, Thomas P. ; Xu, Kailin. / Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia. In: British Journal of Haematology. 2015 ; Vol. 168, No. 3. pp. 371-383.
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abstract = "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.",
author = "Xiaoshen Sun and Hasanali, {Zainul S.} and Allshine Chen and Dianzheng Zhang and Xin Liu and Hong-Gang Wang and Feith, {David J.} and Loughran, {Thomas P.} and Kailin Xu",
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Sun, X, Hasanali, ZS, Chen, A, Zhang, D, Liu, X, Wang, H-G, Feith, DJ, Loughran, TP & Xu, K 2015, 'Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia', British Journal of Haematology, vol. 168, no. 3, pp. 371-383. https://doi.org/10.1111/bjh.13143

Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia. / Sun, Xiaoshen; Hasanali, Zainul S.; Chen, Allshine; Zhang, Dianzheng; Liu, Xin; Wang, Hong-Gang; Feith, David J.; Loughran, Thomas P.; Xu, Kailin.

In: British Journal of Haematology, Vol. 168, No. 3, 01.02.2015, p. 371-383.

Research output: Contribution to journalArticle

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AU - Liu, Xin

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AB - 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.

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