目的:急性髓性白血病(AML)是一种高度异质性和复发性的血液系统恶性肿瘤。尽管出现了新的化疗药物,AML患者完全缓解(CR)仍然不能令人满意。因此,必须发现新的治疗靶点或药物来治疗AML.DNA甲基化和组蛋白修饰等表观遗传变化在AML中起着至关重要的作用。肽基精氨酸脱氨基酶(PAD)是组蛋白脱甲基酶的蛋白质家族,其中PAD2和PAD4的表达在AML患者中被证实升高,因此提示PAD在AML的发展或维持中的潜在作用以及鉴定新治疗靶标的潜力。
方法:用泛PAD抑制剂BB-Cl-脒(BB-Cl-A)体外处理AML细胞。BB-Cl-A可有效诱导AML细胞系凋亡。然而,PAD4特异性抑制剂GSK484没有.
结果:PAD2在AML中起重要作用。此外,我们发现BB-Cl-A可以激活内质网(ER)应激反应,如磷酸化PERK(p-PERK)和eIF2α(p-eIF2α)的增加所证明的。作为内质网应激激活的结果,BB-Cl-A有效诱导AML细胞凋亡。
结论:我们的研究结果表明,PAD2在内质网稳态维持和凋亡预防中起作用。因此,用BB-Cl-A靶向PAD2可能代表治疗AML的新治疗策略.
OBJECTIVE: Acute myeloid leukemia (AML) is a highly heterogeneous and recurrent hematological malignancy. Despite the emergence of novel chemotherapy drugs, AML patients\' complete remission (CR) remains unsatisfactory. Consequently, it is imperative to discover new therapeutic targets or medications to treat AML. Such epigenetic changes like DNA methylation and histone modification play vital roles in AML. Peptidylarginine deminase (PAD) is a protein family of histone demethylases, among which the PAD2 and PAD4 expression have been demonstrated to be elevated in AML patients, thus suggesting a potential role of PADs in the development or maintenance of AML and the potential for the identification of novel therapeutic targets.
METHODS: AML cells were treated in vitro with the pan-PAD inhibitor BB-Cl-Amidine (BB-Cl-A). The AML cell lines were effectively induced into apoptosis by BB-Cl-A. However, the PAD4-specific inhibitor GSK484 did not.
RESULTS: PAD2 played a significant role in AML. Furthermore, we found that BB-Cl-A could activate the endoplasmic reticulum (ER) stress response, as evidenced by an increase in phosphorylated PERK (p-PERK) and eIF2α (p-eIF2α). As a result of the ER stress activation, the BB-Cl-A effectively induced apoptosis in the AML cells.
CONCLUSIONS: Our findings indicated that PAD2 plays a role in ER homeostasis maintenance and apoptosis prevention. Therefore, targeting PAD2 with BB-Cl-A could represent a novel therapeutic strategy for treating AML.