Functional Characterization of D9, a Novel Deazaneplanocin A (DZNep) Analog, in Targeting Acute Myeloid Leukemia (AML).
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| Abstract |
Aberrant epigenetic events contribute to tumorigenesis of all human cancers. Significant efforts are underway in developing new generation of epigenetic cancer therapeutics. Although clinical trials for agents targeting DNA hypermethylation and histone deacetylation have yielded promising results, developing agents that target histone methylation remains to be in the early stage. We and others have previously reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that has a wide range of anticancer effects in various human cancers. Here, focusing on acute myeloid leukemia (AML) as a model, we reported a less toxic analog of DZNep, named D9, which is shown to be efficacious in AML cell lines and patient-derived samples in vitro, as well as AML tumorigenesis in vivo. Gene expression analysis in a panel of AML cell lines treated with D9 identified a set of genes that is associated with D9 sensitivity and implicated in multiple oncogenic signaling pathways. Moreover, we show that D9 is able to deplete the leukemia stem cells (LSC) and abolish chemotherapy-induced LSC enrichment, leading to dramatic elimination of AML cell survival. Thus, D9 appears to be a robust epigenetic compound that may constitute a potential for AML therapy.
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| Authors | Xia Jiang, Cheryl Zi Hui Lim, Zhimei Li, Puay Leng Lee, Siti Maryam J M Yatim, Peiyong Guan, Juntao Li, Jianbiao Zhou, Jingxuan Pan, Wee-Joo Chng, Christina L L Chai, Qiang Yu |
| Journal | PloS one (PLoS One) Vol. 10 Issue 4 Pg. e0122983 ( 2015) ISSN: 1932-6203 [Electronic] United States |
| PMID | 25928216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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