Jan-Ngam Varit, Boontha Siriraj, Tubsuwan Alisa, Wongpalee Somsakul Pop, Fanhchaksai Kanda, Tantiworawit Adisak, Charoenkwan Pimlak, Khamphikham Pinyaphat
Master of Science Program in Medical Technology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
Division of Clinical Microscopy, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
Heliyon. 2024 Sep 18;10(18):e38020. doi: 10.1016/j.heliyon.2024.e38020. eCollection 2024 Sep 30.
Reactivation of fetal hemoglobin (HbF, αγ) potentially alleviates clinical presentation in β-thalassemia. Prolyl hydroxylase domain enzymes (PHDs) play roles in the canonical oxygen-sensing pathway and maintain the stability of cellular hypoxia-inducible factor α (HIF-α) in response to low oxygen levels or hypoxia. Pharmacological inhibition of PHDs has been shown to increase HbF production in erythroid progenitors derived from healthy donors. Here, we demonstrated the relationship between PHD2, the main PHD isoform, and clinical phenotypes in β-thalassemia/HbE disease. Although the targeted sequencing annotated several common variants within , the gene encoding PHD2, none of these variants were located in the functional domains of PHD2 and were irrelevant to the clinical phenotypes. CRISPR-mediated modifications at the functional regions; however, led to significantly reduce PHD2 expression and increase HbF expression levels in severe β-thalassemia erythroblasts. Moreover, these beneficial phenotypes were independent to the two well-known HbF regulators including BCL11A and GATA1. Our findings introduce an additional mechanism for HbF regulation in β-thalassemia and propose that targeting the canonical oxygen-sensing pathway, particularly PHD2 functional domains, might offer a promising therapeutic strategy to β-thalassemia diseases.
胎儿血红蛋白（HbF，αγ）的重新激活可能会缓解β地中海贫血的临床表现。脯氨酰羟化酶结构域酶（PHD）在经典的氧感应途径中发挥作用，并在低氧水平或缺氧情况下维持细胞缺氧诱导因子α（HIF-α）的稳定性。已有研究表明，对PHD进行药理抑制可增加源自健康供体的红系祖细胞中HbF的产生。在此，我们证明了主要的PHD亚型PHD2与β地中海贫血/HbE病临床表型之间的关系。尽管靶向测序标注了编码PHD2的基因内的几个常见变异，但这些变异均不在PHD2的功能域内，且与临床表型无关。然而，在功能区域进行CRISPR介导的修饰可显著降低重度β地中海贫血成红细胞中PHD2的表达，并提高HbF表达水平。此外，这些有益表型独立于包括BCL11A和GATA1在内的两个著名的HbF调节因子。我们的研究结果引入了β地中海贫血中HbF调节的另一种机制，并提出靶向经典的氧感应途径，特别是PHD2功能域，可能为β地中海贫血疾病提供一种有前景的治疗策略。
