Reduced ribosomal protein gene dosage and p53 activation in low-risk myelodysplastic syndrome Journal Article
| Authors: | McGowan, K. A.; Pang, W. W.; Bhardwaj, R.; Perez, M. G.; Pluvinage, J. V.; Glader, B. E.; Malek, R.; Mendrysa, S. M.; Weissman, I. L.; Park, C. Y.; Barsh, G. S. |
| Article Title: | Reduced ribosomal protein gene dosage and p53 activation in low-risk myelodysplastic syndrome |
| Abstract: | Reduced gene dosage of ribosomal protein subunits has been implicated in 5q- myelodysplastic syndrome and Diamond Blackfan anemia, but the cellular and pathophysiologic defects associated with these conditions are enigmatic. Using conditional inactivation of the ribosomal protein S6 gene in laboratory mice, we found that reduced ribosomal protein gene dosage recapitulates cardinal features of the 5q-syndrome, including macrocytic anemia, erythroid hypoplasia, and megakaryocytic dysplasia with thrombocytosis, and that p53 plays a critical role in manifestation of these phenotypes. The blood cell abnormalities are accompanied by a reduction in the number of HSCs, a specific defect in late erythrocyte development, and suggest a disease-specific ontogenetic pathway for megakaryocyte development. Further studies of highly purified HSCs from healthy patients and from those with myelodysplastic syndrome link reduced expression of ribosomal protein genes to decreased RBC maturation and suggest an underlying and common pathophysiologic pathway for additional subtypes of myelodysplastic syndrome. © 2011 by The American Society of Hematology. |
| Keywords: | clinical article; controlled study; unclassified drug; human cell; fluorouracil; nonhuman; animal cell; mouse; phenotype; animals; mice; animal tissue; genetic predisposition to disease; models, biological; cell maturation; animal experiment; animal model; down-regulation; risk factors; drug effect; mutational analysis; protein p53; mice, inbred c57bl; risk assessment; mice, transgenic; myelodysplastic syndrome; blood disease; tumor suppressor protein p53; gene control; blood cell; hematopoiesis; hemizygosity; protein deficiency; blood cell count; gene dosage; myelodysplastic syndromes; thrombocytosis; ribosomal proteins; protein mdm2; ribosome protein; mice, inbred c3h; chromosome 5q; protein s6; protein trp53; erythroid hypoplasia; macrocytic anemia; megakaryocytic dysplasia |
| Journal Title: | Blood |
| Volume: | 118 |
| Issue: | 13 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2011-09-29 |
| Start Page: | 3622 |
| End Page: | 3633 |
| Language: | English |
| DOI: | 10.1182/blood-2010-11-318584 |
| PROVIDER: | scopus |
| PMCID: | PMC3186336 |
| PUBMED: | 21788341 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2011" - "CODEN: BLOOA" - "Source: Scopus" |
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