Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation

Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation

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Abstract 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 metabolic processes.Here, we identify succinate dehydrogenase (SDH) deficiency and over-cumulative succinate as typical features in AML, with iphone 14 price texas a marked function in causing the resistance of AML cells to various anti-cancer therapies.Mechanistically, succinate promotes the accumulation of oncogenic proteins in a manner that precedes transcriptional activation.

This function is mediated by succinate-triggered 730 sunken lake road upregulation of ubiquitin-conjugating enzyme E2M (UBC12) phosphorylation, which impairs its E2 function in cullins neddylation.Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML.Together, we uncover the 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.