Diamond Blackfan anemia 2008–2009: broadening the scope of ribosome biogenesis disorders

Abstract

Purpose of Review-Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by erythroid failure, congenital anomalies and predisposition to cancer. Recently, the notion of DBA as a disorder of ribosome biogenesis has been clarified. Correlations between molecular underpinnings and disease pathophysiology while elusive are beginning to emerge. Advances in these areas will be explored in this review Recent Findings-All known genes mutated in DBA encode ribosomal proteins associated with either the small (RPS) or large (RPL) subunit and in these cases ribosomal protein haploinsufficiency gives rise to the disease. The number of genes affected, their potential interactions with the environment and modifier genes, and the myriad of potential signaling pathways linking abortive ribosome synthesis to cell cycle regulators may all contribute to disease heterogeneity. Genotype/ phenotype relationships emerging over the past year promise to shed light on these complex interrelationships and their role in DBA pathophysiology.Summary-The nosology of DBA has recently expanded to include two distinct disease categories; a classical inherited bone marrow failure syndrome and a "ribosomopathy". The description of DBA as a ribosomopathy has provided a context for scientific inquiry analogous to the description of Fanconi anemia as a disorder of DNA repair.

Reduced ribosomal protein gene dosage and p53 activation in low-risk myelodysplastic syndrome

“…25 Intriguingly, DBA, a congenital BM failure syndrome, exhibits erythroid defects similar to 5qϪ syndrome, and in recent studies researchers suggest that both conditions are caused by reduced dosage of one or more ribosomal protein genes. 2,5 To date, the underlying cellular pathophysiology and potential approaches to treatment for these diseases have been difficult to unravel. 3630 McGOWAN et al BLOOD, 29 SEPTEMBER 2010 ⅐ VOLUME 118, NUMBER 13 For personal use only.…”

“…25 Intriguingly, DBA, a congenital BM failure syndrome, exhibits erythroid defects similar to 5qϪ syndrome, and in recent studies researchers suggest that both conditions are caused by reduced dosage of one or more ribosomal protein genes. 2,5 To date, the underlying cellular pathophysiology and potential approaches to treatment for these diseases have been difficult to unravel. During earlier studies of pigmentary mutations in mice, we realized that reduced dosage of the ribosomal protein genes, Rps6, Rps19, and Rps20, led to activation of p53 in which the differential and specific response of individual cell types in the skin and blood gave rise to a pleiotropic syndrome that was likely relevant to 5qϪ MDS and DBA.…”

“…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.…”

RNA Processing and Ribosome Biogenesis in Bone Marrow Failure Disorders

“…In patients bearing a RPS19 deficiency, the levels of GATA1 were found to be reduced in the erythroid progenitor population while p53 and TNFα expression were increased in the non-erythroid progenitors [18,20] . Inhibition of TNFα in a zebrafish model of RPS19-deficiency was able to rescue the observed anemia, suggesting TNFα expression has a significant role in the observed phenotype [20] .…”

“…DBA is mainly characterized by a profound anemia, but like FA, other congenital defects (growth retardation, cranialfacial abnormalities, defects in the heart and urinary system) are observe in a significant portion of patients (up to 50%). These individuals have an increased incidence of developing MDS and AML as well as some other forms of cancer [1,18] . DBA appears to result from altered ribosomal RNA (rRNA) processing which, in turn, affects ribosome biogenesis of the 40S and 60S ribosomal subunits and alters mRNA processing/transport and translation; thus having pleiotropic effects on cellular growth and survival [18] .…”