文章：

蛋白质组学分析揭示ACSS2为急性髓系白血病提供代谢支持

Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia 

原文发布日期：2024-06-08 

英文摘要：

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by genomic aberrations in oncogenes, cytogenetic abnormalities, and an aberrant epigenetic landscape. Nearly 50% of AML cases will relapse with current treatment. A major source of therapy resistance is the interaction of mesenchymal stroma with leukemic cells resulting in therapeutic protection. We aimed to determine pro-survival/anti-apoptotic protein networks involved in the stroma protection of leukemic cells. Proteomic profiling of cultured primary AML (n = 14) with Hs5 stroma cell line uncovered an up-regulation of energy-favorable metabolic proteins. Next, we modulated stroma-induced drug resistance with an epigenetic drug library, resulting in reduced apoptosis with histone deacetylase inhibitor (HDACi) treatment versus other epigenetic modifying compounds. Quantitative phosphoproteomic probing of this effect further revealed a metabolic-enriched phosphoproteome including significant up-regulation of acetyl-coenzyme A synthetase (ACSS2, S30) in leukemia-stroma HDACi treated cocultures compared with untreated monocultures. Validating these findings, we show ACSS2 substrate, acetate, promotes leukemic proliferation, ACSS2 knockout in leukemia cells inhibits leukemic proliferation and ACSS2 knockout in the stroma impairs leukemic metabolic fitness. Finally, we identify ACSS1/ACSS2-high expression AML subtype correlating with poor overall survival. Collectively, this study uncovers the leukemia-stroma phosphoproteome emphasizing a role for ACSS2 in mediating AML growth and drug resistance. 

摘要翻译：

急性髓系白血病（AML）是一种具有基因组异质性的疾病，其特征包括癌基因的基因组畸变、细胞遗传学异常以及异常的表观遗传状态。在当前治疗手段下，近50%的AML病例会出现复发。治疗抵抗的主要来源是间质基质细胞与白血病细胞的相互作用导致的治疗性保护。我们旨在确定参与基质细胞对白血病细胞保护作用的促生存/抗凋亡蛋白网络。通过对原代AML细胞（n=14）与Hs5基质细胞系共培养的蛋白质组学分析，发现能量代谢相关蛋白表达上调。随后，我们采用表观遗传药物库调控基质诱导的耐药性，发现组蛋白去乙酰化酶抑制剂（HDACi）相较于其他表观遗传修饰化合物能进一步降低细胞凋亡。对这一效应进行的定量磷酸化蛋白质组学分析揭示了富集代谢通路的磷酸化蛋白质组，其中乙酰辅酶A合成酶（ACSS2，S30）在HDACi处理的白血病-基质细胞共培养组中较未处理的单独培养组显著上调。验证实验表明：ACSS2的底物乙酸可促进白血病细胞增殖；白血病细胞中ACSS2基因敲除会抑制其增殖；基质细胞中ACSS2敲除则会损害白血病的代谢适应性。最后，我们发现了ACSS1/ACSS2高表达AML亚型与患者总体生存率降低相关。本研究通过揭示白血病-基质细胞的磷酸化蛋白质组特征，阐明了ACSS2在介导AML生长和耐药性中的关键作用。

原文链接：

Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia