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. (Blood. 2011;118(13):3622-3633) IntroductionMyelodysplastic syndrome (MDS) is a heterogeneous group of blood cell disorders characterized by defective hematopoiesis and increased susceptibility to leukemia; it is thought to involve abnormalities in HSCs. Approximately 50% of affected patients have blood cell cytogenetic abnormalities, of which deletions of chromosome 5q are the most common and portend a favorable prognosis. 1 Identification of causal genes in 5qϪ and other MDS subtypes has been challenging, but recent advances in genetics and genomics have enhanced our understanding of how specific chromosomal alterations and their molecular consequences contribute to the pathogenesis of MDS. 2,3 On the basis of a large-scale RNAi screen, Ebert et al identified RPS14 as a critical gene on 5q whose hemizygosity in BM cells recapitulates many of the features in 5qϪ MDS. 2 Intriguingly, erythroid abnormalities in 5qϪ MDS are similar to those in Diamond Blackfan anemia (DBA), a dominantly inherited disorder in which germline mutations in one allele of either a 40S (encoded by RPS genes) or a 60S (encoded by the RPL genes) ribosomal protein gene have been identified. 4,5 However, there are also important differences between the blood cell phenotypes of the 2 conditions; thrombocytosis and megakaryocytic dysplasia are cardinal features of 5qϪ MDS but not of DBA. Furthermore, recent work from Starczynowski et al suggests that 2 microRNAs are critical mediators of the 5qϪ phenotype because knockdown of these genes in immature hematopoietic cells leads to megakaryocytic dysplasia and thrombocytosis after transplantation in mice. 6 Increased understanding of how ribosomal protein mutations cause disease might provide additional insight into the pathogenesis of MDS and DBA.Spontaneous and induced ribosomal protein mutations have been studied in many model organisms, including yeast, flies, plants, fish, and mice. [7][8][9][10][11][12][13] ...

Loss of Tumor Suppressor RPL5/RPL11 Does Not Induce Cell Cycle Arrest but Impedes Proliferation Due to Reduced Ribosome Content and Translation Capacity

“…Several reports have pointed to p53 as the underlying mechanism of the anemia (49,63), with a recent study showing that p53 levels are increased in RPL11-depleted CD34 ϩ -derived erythroid cells and in bone marrow cells from a limited number of patients harboring RPL11 mutations (64). However, depletion of RPL11 or RPS19 in a p53 Ϫ/Ϫ murine erythroblast cell line revealed severe defects in RPL11 elicit a p53 cell cycle checkpoint in an RPL5/RPL11/5S rRNA-Hdm2-dependent manner.…”

Haploinsufficiency screen highlights two distinct groups of ribosomal protein genes essential for embryonic stem cell fate

“…4A) (13). This p53 response has been hypothesized to represent the cornerstone of ribosomopathies, given that many symptoms of these conditions can be corrected by a simple attenuation of p53 activity (12,14,15).…”

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

“…9,10 Studies on cellular and animal models suggest that unscheduled upregulation of p53 may account for many clinical symptoms associated with ribosomopathies. [11][12][13][14][15][16] There are now evidences that ribosome biogenesis dysfunction also triggers p53-independent mechanisms. [17][18][19] Because bone marrow defects is a frequent clinical manifestation of ribosomopathies, most studies focused on the hematopoietic tissue and less is known about the impact of ribosome biogenesis dysfunction in other organs.…”