High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response

In this study, we investigated the clinical significance and biological insight ofBCAT1 in AML. Using q-PCR, we analyzedBCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. HighBCAT1 expression independently predicts poor prognosis in patients with AML. We also establishedBCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found thatBCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated thatBCAT1 regulates histone methylation by reducing intracellularαKG levels in AML cells. Moreover, high expression ofBCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated thatBCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with highBCAT1 expression.Key messagesHigh expression ofBCAT1 is an independent risk factor for poor prognosis in patients with CN-AML.HighBCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels.H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process.Increased sensitivity ofBCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.
Source: Journal of Molecular Medicine - Category: Molecular Biology Source Type: research