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

S Dutt, A Narla, K Lin, A Mullally… - Blood, The Journal …, 2011 - ashpublications.org
S Dutt, A Narla, K Lin, A Mullally, N Abayasekara, C Megerdichian, FH Wilson, T Currie…
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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.
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