Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation
Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct microenvironment-associated metabolic processes. Here, we identified SDH deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to a wide range of anti-cancer therapies. Mechanistically, succinate promoted the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function was mediated by succinate-triggered upregulation of UBC12 phosphorylation, which impaired its E2 function in cullins neddylation. Notably, decreasing succinate levels by fludarabine could effectively restore the drug sensitivity of SDH-deficient AML PDX. Together, we uncover a novel function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML. Overall design: HL-60 cells were treated with 6 mM succinate for 3 h or 24 h and then harvested. SDHA is knocked down in HL-60 cells using lentiviral infection, followed by two rounds of puromycin selection to establish stable SDHA knockdown cell lines.  RNA sequencing was then actualized and analyzed.