Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No.79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.
Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, China.
J Mol Med (Berl). 2024 Mar;102(3):415-433. doi: 10.1007/s00109-023-02409-1. Epub 2024 Feb 10.
Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.
先前的证据已经证实，支链氨基酸转氨酶-1（BCAT1）是调节支链氨基酸（BCAA）代谢的关键酶，通过限制 αKG 水平和抑制 αKG 依赖性酶家族的活性，在癌症侵袭中发挥作用。然而，BCAT1 在急性髓系白血病（AML）中的致癌作用尚未完全阐明。在这项研究中，我们研究了 BCAT1 在 AML 中的临床意义和生物学见解。使用 q-PCR，我们分析了 332 例新诊断 AML 患者骨髓样本中的 BCAT1 mRNAs。高 BCAT1 表达独立预测 AML 患者预后不良。我们还建立了 BCAT1 敲除（KO）/过表达（OE）AML 细胞系，以探讨潜在的机制。我们发现 BCAT1 通过降低 AML 细胞内的 αKG 水平来影响细胞增殖并调节细胞周期、细胞凋亡和 DNA 损伤/修复过程。此外，我们证明 BCAT1 通过降低细胞内的 αKG 水平来调节组蛋白甲基化，从而调节 AML 细胞中的组蛋白甲基化。此外，BCAT1 高表达增强了 AML 细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂的敏感性，无论是在体内还是体外。我们的研究表明，BCAT1 表达可以作为 AML 患者的可靠预测指标，PARP 抑制剂 BMN673 可作为高 BCAT1 表达患者的有效治疗策略。
高表达的 BCAT1 是 CN-AML 患者预后不良的独立危险因素。AML 中高表达的 BCAT1 限制了细胞内的 αKG 水平，损害了 αKG 依赖性组蛋白去甲基化酶活性，并上调了 H3K9me3 水平。H3K9me3 抑制 ATM 表达并阻断细胞 DNA 损伤修复过程。增加 BCAT1 高表达 AML 对 PARP 抑制剂的敏感性可能可作为 AML 患者的有效治疗策略。
