Targeting SIRT5 By Succinylating Hadha Synergizes with Venetoclax in Acute Myeloid Leukemia

作者：Moran Wang, Wei Shi, Ruiqi Zhu, Donald Small, Li Li, Shengling Ma, Yu Hu · 发表于：Blood · 年份：2023 · DOI：10.1182/blood-2023-178420 · 被引用次数：2 · 研究领域：Histone Deacetylase Inhibitors Research、Protein Degradation and Inhibitors、Acute Myeloid Leukemia Research

Background: Acute myeloid leukemia (AML) is genetically diverse, driven by multiple oncogenic factors. Metabolic dysregulation is a critical vulnerability in AML cells for targeted therapy. BCL2 has been previously reported to maintain mitochondrial oxidative phosphorylation (OXPHOS) in AML cells. One of the mechanisms of action of the combination of venetoclax and azacitidine is to inhibit amino acid metabolism, leading to cell death. Although venetoclax-based treatment regimens have shown promising clinical outcomes in AML patients, treatment resistance has become a newly emerged challenge. Leukemia stem cells isolated from venetoclax-resistant patients exhibit distinctive metabolic features, including elevated nicotinamide metabolism. SIRT5 is an NAD+-dependent deacylase enzyme, and its knockout leads to elevated succinylation of various enzymes involved in OXPHOS. Hence, we hypothesize that inhibiting SIRT5 may augment venetoclax's cytotoxic effect by dampening metabolism. To further elucidate this mechanism, we employed proteome analyses of succinylation to identify specific target molecules regulated by SIRT5. Methods: To determine the effects of combination therapy on cell proliferation, apoptosis, and colony formation, AML cell lines were transduced with lentiviruses carrying either shNC or shSIRT5, or treated with NRD167 (a specific inhibitor of SIRT5), followed by venetoclax treatment. To evaluate the clearance of leukemia cells in vivo, NSG mice were transplanted w...