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 Blood, 24 September 2009, Vol. 114, No. 13, pp. 2733-2743.
Prepublished online as a Blood First Edition Paper on July 28, 2009; DOI 10.1182/blood-2009-03-213496.

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MYELOID NEOPLASIA

Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells

Warren Fiskus1, Yongchao Wang1, Arun Sreekumar1, Kathleen M. Buckley1, Huidong Shi1, Anand Jillella1, Celalettin Ustun1, Rekha Rao1, Pravina Fernandez1, Jianguang Chen1, Ramesh Balusu1, Sanjay Koul1, Peter Atadja2, Victor E. Marquez3, and Kapil N. Bhalla1

1 Medical College of Georgia Cancer Center, Augusta; 2 Novartis Institute for Biomedical Research, Cambridge, MA; and 3 National Institutes of Health, Bethesda, MD

The polycomb repressive complex (PRC) 2 contains 3 core proteins, EZH2, SUZ12, and EED, in which the SET (suppressor of variegation–enhancer of zeste-trithorax) domain of EZH2 mediates the histone methyltransferase activity. This induces trimethylation of lysine 27 on histone H3, regulates the expression of HOX genes, and promotes proliferation and aggressiveness of neoplastic cells. In this study, we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) depletes EZH2 levels, and inhibits trimethylation of lysine 27 on histone H3 in the cultured human acute myeloid leukemia (AML) HL-60 and OCI-AML3 cells and in primary AML cells. DZNep treatment induced p16, p21, p27, and FBXO32 while depleting cyclin E and HOXA9 levels. Similar findings were observed after treatment with small interfering RNA to EZH2. In addition, DZNep treatment induced apoptosis in cultured and primary AML cells. Furthermore, compared with treatment with each agent alone, cotreatment with DZNep and the pan-histone deacetylase inhibitor panobinostat caused more depletion of EZH2, induced more apoptosis of AML, but not normal CD34+ bone marrow progenitor cells, and significantly improved survival of nonobese diabetic/severe combined immunodeficiency mice with HL-60 leukemia. These findings indicate that the combination of DZNep and panobinostat is effective and relatively selective epigenetic therapy against AML cells.


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