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

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. AML1‐ETO can target and epigenetically suppress the novel gene THAP10 directly at the transcriptional level and indirectly at the translational one via miR‐383. This provides mechanistic insight on its role in t(8;21) AML leukemogenesis.
Source: EMBO Molecular Medicine - Category: Molecular Biology Authors: Tags: Research Article Source Type: research