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Abstract：
Acute myeloid leukemia (AML) is the most prevalent type of hematopoietic malignancy. Despite recent therapeutic advancements, the high relapse rate associated with extramedullary involvement remains a challenging issue. Moreover, therapeutic targets that regulate the extramedullary infiltration of AML cells are still not fully elucidated. The Aryl Hydrocarbon Receptor (AHR) is known to influence the progression and migration of solid tumors; however, its role in AML is largely unknown. This study explored the roles of AHR in the invasion and migration of AML cells. We found that suppressed expression of AHR target genes correlated with an elevated relapse rate in AML. Treatment with an AHR agonist on patient-derived AML cells significantly decreased genes associated with leukocyte trans-endothelial migration, cell adhesion, and regulation of the actin cytoskeleton. These results were further confirmed in THP-1 and U937 AML cell lines using AHR agonists (TCDD and FICZ) and inhibitors (SR1 and CH-223191). Treatment with AHR agonists significantly reduced Matrigel invasion, while inhibitors enhanced it, regardless of the Matrigel\'s stiffness. AHR agonists significantly reduced the migration rate and chemokinesis of both cell lines, but AHR inhibitors enhanced them. Finally, we found that the activity of AHR and the expression of NMIIA are negatively correlated. These findings suggest that AHR activity regulates the invasiveness and motility of AML cells, making AHR a potential therapeutic target for preventing extramedullary infiltration in AML.
摘要：
急性髓细胞性白血病（AML）是最常见的造血系统恶性肿瘤。尽管最近的治疗进展，与髓外受累相关的高复发率仍然是一个具有挑战性的问题.此外，调节AML细胞髓外浸润的治疗靶点仍未完全阐明.已知芳基烃受体(AHR)影响实体瘤的进展和迁移;然而,其在AML中的作用在很大程度上是未知的。本研究探讨了AHR在AML细胞侵袭和迁移中的作用。我们发现抑制AHR靶基因的表达与AML的复发率升高相关。AHR激动剂对患者来源的AML细胞的治疗显著降低与白细胞跨内皮迁移相关的基因，细胞粘附，和肌动蛋白细胞骨架的调节。使用AHR激动剂(TCDD和FICZ)和抑制剂(SR1和CH-223191)在THP-1和U937AML细胞系中进一步证实了这些结果。用AHR激动剂治疗可显著减少基质胶侵袭，而抑制剂增强了它，无论基质胶的刚度。AHR激动剂显着降低两种细胞系的迁移率和化学运动，但是AHR抑制剂增强了它们。最后,我们发现AHR的活性与NMIIA的表达呈负相关。这些发现表明AHR活性调节AML细胞的侵袭性和运动性,使AHR成为预防AML髓外浸润的潜在治疗靶点。
