Fig. 8

Proposed mechanism of synergistic action between venetoclax and ATO. Schematic diagram depicting the synergism between venetoclax and ATO in LSC-like leukaemia cells and primary LSCs. Bcl-2 inhibition by venetoclax in LSC-like leukaemia cells leads to the upregulation of Mcl-1, which confers resistance to venetoclax. However, upon combination treatment with venetoclax and ATO, AKT is attenuated and subsequently impairs GSK-3β phosphorylation at Ser9 and activates GSK-3β. This leads to the phosphorylation of Mcl-1 at Ser159, triggering Mcl-1 degradation. The levels of Noxa and Bim, which are normally sequestered by Mcl-1, are elevated upon Mcl-1 degradation and promote caspase-dependent apoptosis associated with Bak activation. In parallel, ERK downregulation attenuates Mcl-1 phosphorylation at Thr163, leading to Mcl-1 destabilisation. The venetoclax and ATO combination also induces the phosphorylation of ATM at Ser1981 and Chk2 at Thr68, promoting cell cycle arrest associated with a robust DNA damage response and apoptosis