Pellagatti Andrea, Hellström-Lindberg Eva, Giagounidis Aristoteles, Perry Janet, Malcovati Luca, Della Porta Matteo G, Jädersten Martin, Killick Sally, Fidler Carrie, Cazzola Mario, Wainscoat James S, Boultwood Jacqueline
LRF Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK.
Br J Haematol. 2008 Jul;142(1):57-64. doi: 10.1111/j.1365-2141.2008.07178.x. Epub 2008 May 8.
We have previously demonstrated haploinsufficiency of the ribosomal gene RPS14, which is required for the maturation of 40S ribosomal subunits and maps to the commonly deleted region, in the 5q- syndrome. Patients with Diamond-Blackfan anaemia (DBA) show haploinsufficiency of the closely related ribosomal protein RPS19, and show a consequent downregulation of multiple ribosomal- and translation-related genes. By analogy with DBA, we have investigated the expression profiles of a large group of ribosomal- and translation-related genes in the CD34(+) cells of 15 myelodysplastic syndrome (MDS) patients with 5q- syndrome, 18 MDS patients with refractory anaemia (RA) and a normal karyotype, and 17 healthy controls. In this three-way comparison, 55 of 579 ribosomal- and translation-related probe sets were found to be significantly differentially expressed, with approximately 90% of these showing lower expression levels in the 5q- syndrome patient group. Using hierarchical clustering, patients with the 5q- syndrome could be separated both from other patients with RA and healthy controls solely on the basis of the deregulated expression of ribosomal- and translation-related genes. Patients with the 5q- syndrome have a defect in the expression of genes involved in ribosome biogenesis and in the control of translation, suggesting that the 5q- syndrome represents a disorder of aberrant ribosome biogenesis.
我们之前已经证明，核糖体基因RPS14单倍剂量不足，它是40S核糖体亚基成熟所必需的，定位于5q-综合征的常见缺失区域。钻石-黑范贫血（DBA）患者表现出密切相关的核糖体蛋白RPS19单倍剂量不足，并导致多个核糖体和翻译相关基因下调。通过与DBA类比，我们研究了15例5q-综合征骨髓增生异常综合征（MDS）患者、18例核型正常的难治性贫血（RA）MDS患者以及17名健康对照者的CD34(+)细胞中一大组核糖体和翻译相关基因的表达谱。在这种三方比较中，579个核糖体和翻译相关探针集中有55个被发现存在显著差异表达，其中约90%在5q-综合征患者组中表达水平较低。使用层次聚类分析，仅根据核糖体和翻译相关基因的失调表达，5q-综合征患者就能与其他RA患者和健康对照者区分开来。5q-综合征患者在核糖体生物合成相关基因的表达以及翻译控制方面存在缺陷，这表明5q-综合征代表了一种核糖体生物合成异常的疾病。
