Martyn Gabriella E, Doerfler Phillip A, Yao Yu, Quinlan Kate G R, Weiss Mitchell J, Crossley Merlin
School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW) Sydney, Sydney, NSW 2052, Australia.
Department of Hematology, St Jude Children's Research Hospital, Memphis, TN 38105-3678, United States.
J Sick Cell Dis. 2024 Oct 3;1(1):yoae008. doi: 10.1093/jscdis/yoae008. eCollection 2024.
Hydroxyurea (HU) is the most widely used therapy for adults and children with sickle cell disease (SCD). It is believed to act largely by inducing the transcription of fetal genes to generate fetal hemoglobin (HbF), which inhibits the pathological polymerization of sickle hemoglobin (HbS). The mechanisms by which hydroxyurea elevates HbF are unclear. We explored the hypothesis that hydroxyurea induces HbF expression by inhibiting the expression of 2 gene repressors, BCL11A and ZBTB7A (also known as LRF), which normally bind the gene promoters to inhibit their expression after birth.
We treated immortalized murine erythroleukemia cells and normal human donor CD34 hematopoietic stem and progenitor cell-derived erythroblasts with hydroxyurea and measured the effects on globin, BCL11A and ZBTB7A protein and mRNA expression.
Treating murine erythroleukemia cells or human CD34 hematopoietic stem and progenitor cell-derived erythroblasts with hydroxyurea reduced the protein levels of BCL11A and ZBTB7A compared to the vehicle-treated control. mRNA levels were reduced in both cell types upon hydroxyurea treatment. However, mRNA levels were only reduced in human CD34 hematopoietic stem and progenitor cell-derived erythroblasts.
Hydroxyurea can act in erythroid cells to reduce the levels and activity of two direct fetal transcriptional repressors with accompanying de-repression of the genes and induction of HbF, which may explain the mechanism of action leading to amelioration of symptoms in SCD patients treated with this drug.
羟基脲（HU）是治疗成人和儿童镰状细胞病（SCD）最广泛使用的疗法。人们认为它主要通过诱导胎儿基因转录以产生胎儿血红蛋白（HbF）来发挥作用，胎儿血红蛋白可抑制镰状血红蛋白（HbS）的病理性聚合。羟基脲升高HbF的机制尚不清楚。我们探讨了这样一种假说，即羟基脲通过抑制两种基因抑制因子BCL11A和ZBTB7A（也称为LRF）的表达来诱导HbF表达，这两种抑制因子通常在出生后与γ-珠蛋白基因启动子结合以抑制其表达。
我们用羟基脲处理永生化小鼠红白血病细胞以及来自正常人类供体CD34造血干细胞和祖细胞的成红细胞，并测量其对珠蛋白、BCL11A和ZBTB7A蛋白及mRNA表达的影响。
与溶剂处理的对照相比，用羟基脲处理小鼠红白血病细胞或来自人类CD34造血干细胞和祖细胞的成红细胞可降低BCL11A和ZBTB7A的蛋白水平。两种细胞类型在羟基脲处理后mRNA水平均降低。然而，只有来自人类CD34造血干细胞和祖细胞的成红细胞的mRNA水平降低。
羟基脲可在红系细胞中发挥作用，降低两种直接的胎儿γ-珠蛋白转录抑制因子的水平和活性，同时解除对γ-珠蛋白基因的抑制并诱导HbF产生，这可能解释了使用该药物治疗的SCD患者症状改善的作用机制。
