Huo Yongliang, Lockhart Jonathan R, Liu Shanrun, Fontenard Suean, Berlett Mike, Ryan Thomas M
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL; and.
Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.
Blood Adv. 2017 Nov 28;1(25):2421-2432. doi: 10.1182/bloodadvances.2017009449.
β-thalassemia is a group of inherited blood disorders that result in defects in β-globin chain production. Cooley anemia (CA), or β-thalassemia major, is the most severe form of the disease and occurs when an individual has mutations in both copies of the adult β-globin gene. Patients with CA fail to make adult hemoglobin, exhibit ineffective erythropoiesis, experience severe anemia, and are transfusion dependent for life. Currently, allogeneic bone marrow transplantation (BMT) is the only cure; however, few patients have suitable donors for this procedure, which has significant morbidity and mortality. In this study, a novel humanized murine model of CA is rescued from lethal anemia by allogeneic BMT in the absence of cytoreductive conditioning. A single intravenous postnatal injection of allogeneic bone marrow results in stable, mixed hematopoietic chimerism. Five months after transplantation, donor cells accounted for approximately 90% of circulating erythrocytes and up to 15% of hematopoietic stem and progenitor cells. Transplanted mice are transfusion independent, have marked improvement of hematological indices, exhibit no growth retardation or signs of graft-versus-host disease, and are fertile. This study describes a method for the consistent engraftment of allogeneic donor hematopoietic cells that rescues a humanized mouse model of CA from lethal anemia, all in the absence of toxic cytoreductive conditioning.
β地中海贫血是一组遗传性血液疾病，会导致β珠蛋白链生成缺陷。库利贫血（CA），即重型β地中海贫血，是该疾病最严重的形式，当个体的成人β珠蛋白基因的两个拷贝都发生突变时就会出现。CA患者无法生成成人血红蛋白，表现出无效造血，患有严重贫血，并且终生依赖输血。目前，异基因骨髓移植（BMT）是唯一的治愈方法；然而，很少有患者有适合进行该手术的供体，而且该手术有显著的发病率和死亡率。在本研究中，一种新型的CA人源化小鼠模型在没有细胞减灭预处理的情况下通过异基因BMT从致命性贫血中获救。出生后单次静脉注射异基因骨髓可导致稳定的混合造血嵌合体。移植五个月后，供体细胞约占循环红细胞的90%，占造血干细胞和祖细胞的比例高达15%。移植后的小鼠不再依赖输血，血液学指标有显著改善，没有生长发育迟缓或移植物抗宿主病的迹象，并且可育。本研究描述了一种在没有毒性细胞减灭预处理的情况下使异基因供体造血细胞持续植入的方法，该方法可将CA人源化小鼠模型从致命性贫血中拯救出来。
