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 Y ，Ning Q ，Shi J ，Chen Y ，Jiang M ，Gao L ，Huang W ，Jing Y ，Huang S ，Liu A ，Hu Z ，Liu D ，Wang L ，Nervi C ，Dai Y ，Zhang MQ ，Yu L ... -  《-》

Epigenetic silencing of miR564 contributes to the leukemogenesis of t(8;21) acute myeloid leukemia.

The AML1-ETO oncoprotein, which results from t(8;21) translocation, is considered an initial event of t(8;21) acute myeloid leukemia (AML). However, the precise mechanisms of the oncogenic activity of AML1-ETO is yet to be fully determined. The present study demonstrates that AML1-ETO triggers the heterochromatic silencing of microRNA-564 (miR564) by binding at the AML1 binding site along the miR564 promoter region and recruiting chromatin-remodeling enzymes. Suppression of miR564 enhances the oncogenic activity of the AML1-ETO oncoprotein by directly inhibiting the expression of CCND1 and the DNMT3A genes. Ectopic expression of miR564 can induce retardation of G1/S transition, reperform differentiation, promote apoptosis, as well as inhibit the proliferation and colony formation of AML1-ETO+ leukemia cells in vitro. Enhanced miR564 levels can significantly inhibit the tumor proliferation of t(8;21)AML in vivo. We first identify an unexpected and important epigenetic circuitry of AML1-ETO/miR564/CCND1/DNMT3A that contributes to the leukemogenesis in vitro/vivo of AML1-ETO+ leukemia, indicating that miR564 enhancement could provide a potential therapeutic method for AML1-ETO+ leukemia.

Yang E ，Guan W ，Gong D ，Gao X ，Han C ，Zhang J ，Wang H ，Wang M ，Li Y ，Yu L ... -  《-》

Epigenetic silencing of microRNA-193a contributes to leukemogenesis in t(8;21) acute myeloid leukemia by activating the PTEN/PI3K signal pathway.

Li Y ，Gao L ，Luo X ，Wang L ，Gao X ，Wang W ，Sun J ，Dou L ，Li J ，Xu C ，Wang L ，Zhou M ，Jiang M ，Zhou J ，Caligiuri MA ，Nervi C ，Bloomfield CD ，Marcucci G ，Yu L ... -  《-》

An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells.

Zaidi SK ，Perez AW ，White ES ，Lian JB ，Stein JL ，Stein GS ... -  《Oncotarget》

Epigenetic Silencing of Eyes Absent 4 Gene by Acute Myeloid Leukemia 1-Eight-twenty-one Oncoprotein Contributes to Leukemogenesis in t(8;21) Acute Myeloid Leukemia.

Huang S ，Jiang MM ，Chen GF ，Qian K ，Gao HH ，Guan W ，Shi JL ，Liu AQ ，Liu J ，Wang BH ，Li YH ，Yu L ... -  《-》