Direct inhibition of dioxygenases TET1 by the rheumatoid arthritis drug auranofin selectively induces cancer cell death in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is a type of hematologic tumor with malignant proliferation of hematopoietic progenitor cells. However, traditional clinical treatment of T-ALL included chemotherapy and stem cell transplantation always lead to recurrence and poor prognosis, thus new therapeutic targets and drugs are urgently needed for T-ALL treatment. In this study, we showed that TET1 (ten-eleven translocation 1), a key participant of DNA epigenetic control, which catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to modulate gene expression, was highly upregulated in human T-ALL and negatively correlated with the prognosis of patients. Knockdown of TET1 suppressed T-ALL growth and progression, suggesting that TET1 inhibition maybe an effective way to fight T-ALL via DNA epigenetic modulation. Combining structure-guided virtual screening and cell-based high-throughput screening of FDA-approved drug library, we discovered that auranofin, a gold-containing compound, is a potent TET1 inhibitor. Auranofin inhibited the catalytic activity of TET1 through competitive binding to its substrates binding pocket and thus downregulated the genomic level of 5hmC marks and particularly epigenetically reprogramed the expression of oncogene c-Myc in T-ALL in TET1-dependent manner and resulted in suppression of T-ALL in vitro and in vivo. These results revealed that TET1 is a potential therapeutic target in human T-ALL and elucidated the mechanism that TET1 inhibitor auranofin suppressed T-ALL through the TET1/5hmC/c-Myc signaling pathway. Our work thus not only provided mechanism insights for T-ALL treatment, but also discovered potential small molecule therapeutics for T-ALL.