Loss of Hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndrome
Loss of Hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndrome
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DOI：
10.1182/blood-2004-03-1089
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发表时间：
2005-05-01
期刊：
影响因子：
20.3
通讯作者：
Rosenthal, A
中科院分区：
文献类型：
--
作者：
Craven, SE;French, D;Rosenthal, A
骨髓增生异常综合征 (MDS) 包括一组通常致命的异质性造血干细胞疾病，目前尚无治愈方法或标准治疗方法。 MDS 的复杂核型和多步骤性质严重限制了致病基因突变的识别，从而限制了对新的、更有效的疗法的了解。在这里，我们描述了一种具有发育性血液缺陷的斑马鱼突变体 crimsonless (crs)，它密切再现了 MDS 的无效造血功能，包括贫血、发育不良、血细胞凋亡增加和多系血细胞减少。通过定位克隆、拯救和吗啉代敲除实验，我们证明crs编码保守的线粒体基质伴侣HSPA9B，其在底物结合域内含有甘氨酸到谷氨酸的取代。这种突变会损害线粒体功能，在血细胞中明显产生氧化应激和细胞凋亡。因此，我们确定了 Hspa9b 在造血中的重要作用，并表明 HSPA9B 的特异性缺失和线粒体功能障碍通常与 MDS 的发病机制有关。 (c) 2005 年，美国血液学会。
Myelodysplastic syndrome (MDS) comprises a heterogeneous group of often-fatal hematopoietic stem cell disorders for which neither curative nor standard treatment exists. The complex karyotypes and multistep nature of MDS have severely restricted the identification of causative genetic mutations and thus limited insight into new and more effective therapies. Here we describe a zebrafish mutant crimsonless (crs) with a developmental blood defect that closely recapitulates the ineffective hematopoiesis of MDS including anemia, dysplasia, increased blood cell apoptosis, and multilineage cytopenia. By positional cloning, rescue, and morpholino knockdown experiments, we demonstrate that crs encodes a conserved mitochondrial matrix chaperone HSPA9B containing a glycine-to-glutamate substitution within the substrate-binding domain. This mutation compromises mitochondrial function, producing oxidative stress and apoptosis distinctly in blood cells. Thus, we identify an essential role for Hspa9b in hematopoiesis and implicate both loss of HSPA9B specifically and mitochondrial dysfunction generally in the pathogenesis of the MDS. (c) 2005 by The American Society of Hematology.