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.

针对急性髓系白血病（AML）细胞的代谢依赖性是一种有前景的治疗策略。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) 发生显着改变。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，我们发现两种核苷类似物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，而蛋氨酸-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，FDA 最近批准用于治疗 AML 的 BCL-2 抑制剂 Venetoclax (VEN) 可显着降低 AML 细胞内蛋氨酸的水平。基于这些发现，我们假设 8CA 或 8AA 与 VEN 组合可以有效靶向 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 协同减少 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 AML 治疗具有广阔的前景，并为我们最近启动的临床试验提供了强有力的理由。