Leukemia ( IF 12.8 ) Pub Date : 2024-04-20 , DOI: 10.1038/s41375-024-02222-w
Jiamin Guo 1, 2 , Ralf Buettner 2 , Li Du 2 , Zhenlong Li 2 , Wei Liu 2 , Rui Su 3 , Zhenhua Chen 3 , Yuan Che 3 , Yi Zhang 4 , Rui Ma 2 , Le Xuan Truong Nguyen 5 , Roger E Moore 6 , Pathak Khyatiben 6, 7 , Min-Hsuan Chen 8 , Pirrotte Patrick 6, 7 , Xiwei Wu 8 , Guido Marcucci 5 , Lili Wang 3 , David Horne 9 , Jianjun Chen 3 , Yanzhong Yang 4 , Steven T Rosen 2
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Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.
中文翻译:

8-Cl-Ado 和 8-NH2-Ado 与维奈托克协同作用,靶向急性髓性白血病中的蛋氨酸-MAT2A-SAM 轴
靶向急性髓性白血病 (AML) 细胞的代谢依赖性是一种很有前途的治疗策略。特别是,与健康血细胞相比,AML 细胞中的半胱氨酸和蛋氨酸代谢途径 (C/M) 发生了显著变化。此外,蛋氨酸已被确定为 AML 细胞的主要氨基酸依赖性之一。通过 RNA-seq,我们发现两个核苷类似物 8-氯腺苷 (8CA) 和 8-氨基腺苷 (8AA) 显着抑制 AML 细胞中的 C/M 通路,蛋氨酸-腺苷转移酶-2A (MAT2A) 是最显着下调的基因之一。此外,质谱分析显示,Venetoclax (VEN) 是一种最近被 FDA 批准用于治疗 AML 的 BCL-2 抑制剂,可显著降低 AML 细胞中蛋氨酸的细胞内水平。基于这些发现,我们假设 8CA 或 8AA 与 VEN 相结合可以有效地靶向 AML 中的蛋氨酸-MAT2A-S-腺苷-蛋氨酸 (SAM) 轴。我们的结果表明,VEN 和 8CA/8AA 协同降低 SAM 生物合成,并在体内和体外有效靶向 AML 细胞。这些发现表明,通过抑制蛋氨酸-MAT2A-SAM 轴,将 8CA/8AA 和 VEN 联合用于治疗 AML 的潜力很大,并为我们最近启动的临床试验提供了强有力的理由。