A novel epigenetic AML1-ETO/THAP10/miR-383 mini-circuitry contributes to t(8;21) leukaemogenesis.
DNA methylation patterns are frequently deregulated in t(8;21) acute myeloid leukaemia (AML), but little is known of the mechanisms by which specific gene sets become aberrantly methylated. Here, we found that the promoter DNA methylation signature of t(8;21)+ AML blasts differs from that of t(8;21)- AMLs. This study demonstrated that a novel hypermethylated zinc finger-containing protein, THAP10, is a target gene and can be epigenetically suppressed by AML1-ETO at the transcriptional level in t(8;21) AML. Our findings also show that THAP10 is a bona fide target of miR-383 that can be epigenetically activated by the AML1-ETO recruiting co-activator p300. In this study, we demonstrated that epigenetic suppression of THAP10 is the mechanistic link between AML1-ETO fusion proteins and tyrosine kinase cascades. In addition, we showed that THAP10 is a nuclear protein that inhibits myeloid proliferation and promotes differentiation both in vitro and in vivo Altogether, our results revealed an unexpected and important epigenetic mini-circuit of AML1-ETO/THAP10/miR-383 in t(8;21) AML, in which epigenetic suppression of THAP10 predicts a poor clinical outcome and represents a novel therapeutic target.
['Li|Yonghui|Y|0000-0001-6782-7473', 'Ning|Qiaoyang|Q|', 'Shi|Jinlong|J|', 'Chen|Yang|Y|', 'Jiang|Mengmeng|M|', 'Gao|Li|L|', 'Huang|Wenrong|W|', 'Jing|Yu|Y|', 'Huang|Sai|S|', 'Liu|Anqi|A|', 'Hu|Zhirui|Z|', 'Liu|Daihong|D|', 'Wang|Lili|L|', 'Nervi|Clara|C|', 'Dai|Yun|Y|', 'Zhang|Michael Q|MQ|', 'Yu|Li|L|0000-0001-6872-2665']
D000818:Animals D063646:Carcinogenesis D045744:Cell Line, Tumor D050676:Core Binding Factor Alpha 2 Subunit D019175:DNA Methylation D004268:DNA-Binding Proteins D004195:Disease Models, Animal D015536:Down-Regulation D044127:Epigenesis, Genetic D005260:Female D064593:Heterografts D006801:Humans D015470:Leukemia, Myeloid, Acute D008807:Mice, Inbred BALB C D035683:MicroRNAs D011401:Promoter Regions, Genetic D000075142:RUNX1 Translocation Partner 1 Protein
epigenetics THAP10 AML1‐ETO miR‐383 t(8 21) AML