Work

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

Year: 2024

Type: article

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 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 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. The underlying mechanisms for drug resistance in Acute Myeloid Leukemia (AML) are not completely understood. Here, the authors show that succinate accumulation, associated with succinate dehydrogenase deficiency, impairs the activity of the ubiquitin-conjugating enzyme UBC12 leading to tumor-promoting protein accumulation and drug resistance in AML.

Source: Nature Communications

DOI: 10.1038/s41467-024-53398-9