Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia
Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia
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DOI：
10.1634/stemcells.2005-0554
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发表时间：
2006-09-01
期刊：
影响因子：
5.2
通讯作者：
Beggs, Alan H.
中科院分区：
文献类型：
--
作者：
Gazda, Hanna T.;Kho, Alvin T.;Beggs, Alan H.
Diamond-Blackfan贫血（DBA）是一种广泛的发育性疾病，其特征是贫血、骨髓（BM）成红细胞减少和恶性肿瘤发病率增加。核糖体蛋白基因S19（RPS 19）突变在DBA患者中的发生率约为25%，但RPS 19在DBA发病机制中的作用尚不清楚。使用全局基因表达分析，我们比较了来自RPS 19突变个体和对照个体的高度纯化的多潜能、红系和髓系BM祖细胞。我们发现几个核糖体蛋白基因在所有DBA祖细胞下调。凋亡基因，如TNFRSF 10 B和FAS，转录控制基因，包括红细胞生成转录因子MYB（编码c-myb），和翻译基因的极大失调，主要是在患病的红系细胞。癌症相关基因，包括RAS家族癌基因和肿瘤抑制基因，在所有患病的祖细胞中显著失调。此外，我们的研究结果提供的证据表明，RPS 19突变导致多个核糖体蛋白基因的下调，以及下调基因参与DBA细胞中的翻译。总之，癌症相关基因表达的改变表明DBA恶性肿瘤的分子基础。c-myb表达的下调导致基因敲除小鼠胎肝红细胞生成的完全失败，表明RPS 19突变与DBA中红细胞生成减少之间存在联系。
Diamond-Blackfan anemia (DBA) is a broad developmental disease characterized by anemia, bone marrow (BM) erythroblastopenia, and an increased incidence of malignancy. Mutations in ribosomal protein gene S19 (RPS19) are found in similar to 25% of DBA patients; however, the role of RPS19 in the pathogenesis of DBA remains unknown. Using global gene expression analysis, we compared highly purified multipotential, erythroid, and myeloid BM progenitors from RPS19 mutated and control individuals. We found several ribosomal protein genes downregulated in all DBA progenitors. Apoptosis genes, such as TNFRSF10B and FAS, transcriptional control genes, including the erythropoietic transcription factor MYB (encoding c-myb), and translational genes were greatly dysregulated, mostly in diseased erythroid cells. Cancer-related genes, including RAS family oncogenes and tumor suppressor genes, were significantly dysregulated in all diseased progenitors. In addition, our results provide evidence that RPS19 mutations lead to codownregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in translation in DBA cells. In conclusion, the altered expression of cancer-related genes suggests a molecular basis for malignancy in DBA. Downregulation of c-myb expression, which causes complete failure of fetal liver erythropoiesis in knockout mice, suggests a link between RPS19 mutations and reduced erythropoiesis in DBA.