MicroRNAs (miRNAs) and N⁶-methyladenosine (m⁶A) are known to serve as key regulators of acute myeloid leukemia (AML). Our previous microarray analysis indicated miR-550-1 was significantly downregulated in AML. The specific biological roles of miR-550-1 and its indirect interactions and regulation of m⁶A in AML, however, remain poorly understood. At the present study, we found that miR-550-1 was significantly down-regulated in primary AML samples from human patients, likely owing to hypermethylation of the associated CpG islands. When miR-550-1 expression was induced, it impaired AML cell proliferation both in vitro and in vivo, thus suppressing tumor development. When ectopically expressed, miR-550-1 drove the G0/1 cell cycle phase arrest, differentiation, and apoptotic death of affected cells. We confirmed mechanistically that WW-domain containing transcription regulator-1 (WWTR1) gene was a downstream target of miR-550-1. Moreover, we also identified Wilms tumor 1-associated protein (WTAP), a vital component of the m⁶A methyltransferase complex, as a target of miR-550-1. These data indicated that miR-550-1 might mediate a decrease in m⁶A levels via targeting WTAP, which led to a further reduction in WWTR1 stability. Using gain- and loss-of-function approaches, we were able to determine that miR-550-1 disrupted the proliferation and tumorigenesis of AML cells at least in part via the direct targeting of WWTR1. Taken together, our results provide direct evidence that miR-550-1 acts as a tumor suppressor in the context of AML pathogenesis, suggesting that efforts to bolster miR-550-1 expression in AML patients may thus be a viable clinical strategy to improve patient outcomes.

中文翻译：

---

miR-550-1 通过河马信号通路在急性髓细胞白血病中发挥肿瘤抑制作用

已知MicroRNA (miRNA) 和 N ⁶ -甲基腺苷 (m ⁶ A) 可作为急性髓性白血病 (AML) 的关键调节剂。我们之前的微阵列分析表明 miR-550-1 在 AML 中显着下调。然而，miR-550-1 的特定生物学作用及其对 m ⁶ A 在 AML 中的间接相互作用和调节仍然知之甚少。在本研究中，我们发现人类患者的原发性 AML 样本中 miR-550-1 显着下调，这可能是由于相关 CpG 岛的高甲基化。当诱导 miR-550-1 表达时，它会在体外和体内损害 AML 细胞增殖，从而抑制肿瘤的发展。当异位表达时，miR-550-1 驱动受影响细胞的 G0/1 细胞周期期停滞、分化和凋亡。我们从机制上证实了含有转录调节因子 1 ( WWTR1 ) 基因的 WW 结构域是 miR-550-1 的下游靶标。此外，我们还确定了 Wilms 肿瘤 1 相关蛋白 ( WTAP )，它是 m ⁶ A 甲基转移酶复合物的重要成分，作为 miR-550-1 的靶标。这些数据表明 miR-550-1 可能通过靶向WTAP介导 m ⁶ A 水平的降低，从而导致 WWTR1 的进一步降低稳定。使用增益和功能丧失方法，我们能够确定 miR-550-1 至少部分通过直接靶向 WWTR1 破坏了 AML 细胞的增殖和肿瘤发生。总之，我们的结果提供了直接证据表明 miR-550-1 在 AML 发病机制中充当肿瘤抑制因子，这表明加强 AML 患者中 miR-550-1 表达的努力可能是改善患者的可行临床策略结果。