Functional Characterization of D9, a Novel Deazaneplanocin A (DZNep) Analog, in Targeting Acute Myeloid Leukemia (AML).
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.
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, 138672, Singapore.
Xia
X
Jiang
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, 138672, Singapore.
Cheryl Zi Hui
CZ
Lim
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, 138672, Singapore.
Zhimei
Z
Li
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, 138672, Singapore.
Puay Leng
PL
Lee
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, 138672, Singapore.
Siti Maryam J M
SM
Yatim
Computational and Systems Biology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, 138672, Singapore.
Peiyong
P
Guan
Computational and Systems Biology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, 138672, Singapore.
Juntao
J
Li
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
Jianbiao
J
Zhou
Department of Pathophysiology, School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, 510089, China.
Jingxuan
J
Pan
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore; Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Wee-Joo
WJ
Chng
Institute of Chemical and Engineering Sciences, 8 Biomedical Grove, Neuros #07-01, Singapore, 138665, Singapore; Department of Pharmacy, 18 Science Drive 4, National University of Singapore, Singapore 117543.
Christina L L
CL
Chai
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, 138672, Singapore; Cancer Institute, Jinan University, Guangzhou, 510632, China; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
Qiang
Q
Yu
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016503:Drug Delivery Systems; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
D000241:Adenosine