Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells

• Published in: Blood Vol. 117; no. 9; pp. 2567 - 2576
• Main Authors: Dutt, Shilpee, Narla, Anupama, Lin, Katherine, Mullally, Ann, Abayasekara, Nirmalee, Megerdichian, Christine, Wilson, Frederick H., Currie, Treeve, Khanna-Gupta, Arati, Berliner, Nancy, Kutok, Jeffery L., Ebert, Benjamin L.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 03.03.2011; Americain Society of Hematology; American Society of Hematology
• Series: Plenary Paper
• Subjects: Anemia, Diamond-Blackfan - genetics; Anemia, Diamond-Blackfan - pathology; Anemia, Macrocytic - genetics; Anemia, Macrocytic - pathology; Animals; Benzothiazoles - pharmacology; Biological and medical sciences; Cell Cycle - drug effects; Cell Lineage - drug effects; Cell Nucleolus - drug effects; Cell Nucleolus - metabolism; Chromosome Deletion; Chromosomes, Human, Pair 5 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - metabolism; Erythroid Precursor Cells - pathology; Haploinsufficiency - genetics; Hematologic and hematopoietic diseases; Hematopoiesis - drug effects; Humans; Imidazoles - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Piperazines - metabolism; Plenary Paper; Protein Binding - drug effects; Proto-Oncogene Proteins c-mdm2 - metabolism; Ribosomal Proteins - deficiency; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; RNA, Small Interfering - metabolism; Toluene - analogs & derivatives; Toluene - pharmacology; Tumor Suppressor Protein p53 - metabolism; Erythropoiesis; Human; TP53 Gene; Erythroid cell; Hematology; Stem cell; Ribosomal DNA; Loss of heterozygosity; Hematopoietic cell; Ribosomal protein; Tumor suppressor gene
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-07-295238

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.