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A novel epigenetic AML1-ETO/THAP10/miR-383 mini-circuitry contributes to t(8;21) leukaemogenesis.


ABSTRACT: 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.

SUBMITTER: Li Y 

PROVIDER: S-EPMC5577530 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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A novel epigenetic <i>AML1-ETO/THAP10/miR-383</i> mini-circuitry contributes to t(8;21) leukaemogenesis.

Li Yonghui Y   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  

EMBO molecular medicine 20170701 7


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)<sup>+</sup> AML blasts differs from that of t(8;21)<sup>-</sup> 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 tran  ...[more]

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