Article

Defective Ribosomal Protein Gene Expression Alters Transcription, Translation, Apoptosis, and Oncogenic Pathways in Diamond-Blackfan Anemia

University of Gdansk, Danzig, Pomeranian Voivodeship, Poland
Stem Cells (Impact Factor: 6.52). 10/2006; 24(9):2034-44. DOI: 10.1634/stemcells.2005-0554
Source: PubMed

ABSTRACT

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 approximately 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.

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    • "Abnormal expression of genes related to apoptosis was also reported in bone marrow CD34 + cells isolated from three DBA patients with mutations in RPS19 and in remission from the disease (Gazda et al., 2006), and in a previous study by our group focused on unraveling the gene expression alterations in fibroblasts isolated from DBA patients with RPS19 mutations (Avondo et al., 2009). Moreover, a large cluster of significantly underexpressed RPs was described in these two reports (Avondo et al., 2009; Gazda et al., 2006). On the contrary, both the present study and a previous one which examined RPS19-deficient TF1 cells showed normal levels of RP mRNAs, with the exception of RPL3 (Badhai et al., 2009, Table S1). "
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    ABSTRACT: Defects in genes encoding ribosomal proteins cause Diamond Blackfan Anemia (DBA), a red cell aplasia often associated with physical abnormalities. Other bone marrow failure syndromes have been attributed to defects in ribosomal components but the link between erythropoiesis and the ribosome remains to be fully defined. Several lines of evidence suggest that defects in ribosome synthesis lead to “ribosomal stress” with p53 activation and either cell cycle arrest or induction of apoptosis. Pathways independent of p53 have also been proposed to play a role in DBA pathogenesis. We took an unbiased approach to identify p53-independent pathways activated by defects in ribosome synthesis by analyzing global gene expression in various cellular models of DBA. Ranking-Principal Component Analysis (Ranking-PCA) was applied to the identified datasets to determine whether there are common sets of genes whose expression is altered in these different cellular models. We observed consistent changes in the expression of genes involved in cellular amino acid metabolic process, negative regulation of cell proliferation and cell redox homeostasis. These data indicate that cells respond to defects in ribosome synthesis by changing the level of expression of a limited subset of genes involved in critical cellular processes. Moreover, our data support a role for p53-independent pathways in the pathophysiology of DBA.
    Full-text · Article · Jul 2014 · Gene
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    • "Abnormal expression of genes related to apoptosis was also reported in bone marrow CD34 + cells isolated from three DBA patients with mutations in RPS19 and in remission from the disease (Gazda et al., 2006), and in a previous study by our group focused on unraveling the gene expression alterations in fibroblasts isolated from DBA patients with RPS19 mutations (Avondo et al., 2009). Moreover, a large cluster of significantly underexpressed RPs was described in these two reports (Avondo et al., 2009; Gazda et al., 2006). On the contrary, both the present study and a previous one which examined RPS19-deficient TF1 cells showed normal levels of RP mRNAs, with the exception of RPL3 (Badhai et al., 2009, Table S1). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Defects in genes encoding ribosomal proteins cause Diamond Blackfan Anemia (DBA), a red cell aplasia often associated with physical abnormalities. Other bone marrow failure syndromes have been attributed to defects in ribosomal components but the link between erythropoiesis and the ribosome remains to be fully defined. Several lines of evidence suggest that defects in ribosome synthesis lead to “ribosomal stress” with p53 activation and either cell cycle arrest or induction of apoptosis. Pathways independent of p53 have also been proposed to play a role in DBA pathogenesis. We took an unbiased approach to identify p53-independent pathways activated by defects in ribosome synthesis by analyzing global gene expression in various cellular models of DBA. Ranking-Principal Component Analysis (Ranking-PCA) was applied to the identified datasets to determine whether there are common sets of genes whose expression is altered in these different cellular models. We observed consistent changes in the expression of genes involved in cellular amino acid metabolic process, negative regulation of cell proliferation and cell redox homeostasis. These data indicate that cells respond to defects in ribosome synthesis by changing the level of expression of a limited subset of genes involved in critical cellular processes. Moreover, our data support a role for p53-independent pathways in the pathophysiology of DBA.
    Full-text · Article · May 2014 · Gene
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    • "These data were compared with data about the defective expression of genes for ribosomal proteins and translation-related factors in DBA published by Pellagatti et al. [50]. Three genes (RPL28, RPS14, and EEF1D) expression was found downregulated in both diseases (MDS 5q-syndrome and DBA) [50] [51]. "
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    ABSTRACT: Myelodysplastic syndrome (MDS) with interstitial deletion of a segment of the long arm of chromosome 5q [del(5q)] is characterized by bone marrow erythroid hyperplasia, atypical megakaryocytes, thrombocythemia, refractory anemia, and low risk of progression to acute myeloid leukemia (AML) compared with other types of MDS. The long arm of chromosome 5 contains two distinct commonly deleted regions (CDRs). The more distal CDR lies in 5q33.1 and contains 40 protein-coding genes and genes coding microRNAs (miR-143, miR-145). In 5q-syndrome one allele is deleted that accounts for haploinsufficiency of these genes. The mechanism of erythroid failure appears to involve the decreased expression of the ribosomal protein S14 (RPS14) gene and the upregulation of the p53 pathway by ribosomal stress. Friend leukemia virus integration 1 (Fli1) is one of the target genes of miR145. Increased Fli1 expression enables effective megakaryopoiesis in 5q-syndrome.
    Full-text · Article · Feb 2012
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