State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
Cell Death Dis. 2020 Feb 19;11(2):135. doi: 10.1038/s41419-020-2331-5.
Diamond-Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome, characterized by red blood cell aplasia, developmental abnormalities, and enhanced risk of malignancy. However, the underlying pathogenesis of DBA is yet to be understood. Recently, mutations in the gene encoding ribosomal protein (RP) L18 were identified in DBA patients. RPL18 is a crucial component of the ribosomal large subunit but its role in hematopoiesis remains unknown. To genetically model the ribosomal defect identified in DBA, we generated a rpl18 mutant line in zebrafish, using CRISPR/Cas9 system. Molecular characterization of this mutant line demonstrated that Rpl18 deficiency mirrored the erythroid defects of DBA, namely a lack of mature red blood cells. Rpl18 deficiency caused an increase in p53 activation and JAK2-STAT3 activity. Furthermore, we found inhibitors of JAK2 or STAT3 phosphorylation could rescue anemia in rpl18 mutants. Our research provides a new in vivo model of Rpl18 deficiency and suggests involvement of signal pathway of JAK2-STAT3 in the DBA pathogenesis.
Diamond-Blackfan 贫血（DBA）是一种罕见的遗传性骨髓衰竭综合征，其特征为红细胞生成障碍、发育异常和恶性肿瘤风险增加。然而，DBA 的发病机制尚不清楚。最近，在 DBA 患者中发现了编码核糖体蛋白（RP）L18 的基因突变。RPL18 是核糖体大亚基的关键组成部分，但它在造血中的作用尚不清楚。为了对 DBA 中鉴定出的核糖体缺陷进行基因建模，我们使用 CRISPR/Cas9 系统在斑马鱼中生成了 rpl18 突变体系。该突变体系的分子特征表明，Rpl18 缺陷反映了 DBA 的红细胞缺陷，即缺乏成熟的红细胞。Rpl18 缺陷导致 p53 激活和 JAK2-STAT3 活性增加。此外，我们发现 JAK2 或 STAT3 磷酸化抑制剂可挽救 rpl18 突变体的贫血。我们的研究提供了 Rpl18 缺陷的新体内模型，并表明 JAK2-STAT3 信号通路参与了 DBA 的发病机制。
