Abstract
Haploinsufficiency for ribosomal protein genes has been implicated in the pathophysiology of Diamond-Blackfan anemia (DBA) and the 5q-syndrome, a subtype of myelodysplastic syndrome. The p53 pathway is activated by ribosome dysfunction, but the molecular basis for selective impairment of the erythroid lineage in disorders of ribosome function has not been determined. We found that p53 accumulates selectively in the erythroid lineage in primary human hematopoietic progenitor cells after expression of shRNAs targeting RPS14, the ribosomal protein gene deleted in the 5q-syndrome, or RPS19, the most commonly mutated gene in DBA. Induction of p53 led to lineage-specific accumulation of p21 and consequent cell cycle arrest in erythroid progenitor cells. Pharmacologic inhibition of p53 rescued the erythroid defect, whereas nutlin-3, a compound that activates p53 through inhibition of HDM2, selectively impaired erythropoiesis. In bone marrow biopsies from patients with DBA or del(5q) myelodysplastic syndrome, we found an accumulation of nuclear p53 staining in erythroid progenitor cells that was not present in control samples. Our findings indicate that the erythroid lineage has a low threshold for the induction of p53, providing a basis for the failure of erythropoiesis in the 5q-syndrome, DBA, and perhaps other bone marrow failure syndromes.
© 2011 by The American Society of Hematology
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anemia, Diamond-Blackfan / genetics
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Anemia, Diamond-Blackfan / pathology
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Anemia, Macrocytic / genetics
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Anemia, Macrocytic / pathology
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Animals
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Benzothiazoles / pharmacology
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Cell Cycle / drug effects
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Cell Lineage / drug effects
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Cell Nucleolus / drug effects
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Cell Nucleolus / metabolism
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Chromosome Deletion
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Chromosomes, Human, Pair 5 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Erythroid Precursor Cells / drug effects
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Erythroid Precursor Cells / metabolism*
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Erythroid Precursor Cells / pathology
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Haploinsufficiency / genetics*
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Hematopoiesis / drug effects
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Humans
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Imidazoles / metabolism
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Mice
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Mice, Inbred BALB C
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Myelodysplastic Syndromes / genetics
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Myelodysplastic Syndromes / pathology
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Piperazines / metabolism
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Protein Binding / drug effects
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Proto-Oncogene Proteins c-mdm2 / metabolism
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RNA, Small Interfering / metabolism
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Ribosomal Proteins / deficiency
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Ribosomal Proteins / genetics*
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Ribosomal Proteins / metabolism
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Toluene / analogs & derivatives
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Toluene / pharmacology
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Benzothiazoles
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Cyclin-Dependent Kinase Inhibitor p21
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Imidazoles
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Piperazines
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RNA, Small Interfering
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Ribosomal Proteins
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Tumor Suppressor Protein p53
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ribosomal protein L11
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ribosomal protein S14
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ribosomal protein S19
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Toluene
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nutlin 3
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pifithrin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
Supplementary concepts
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Chromosome 5q Deletion Syndrome