Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis

Abstract

Diamond-Blackfan anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by erythroid failure, congenital anomalies, and a predisposition to cancer. Faulty ribosome biogenesis, resulting in proapoptotic erythropoiesis leading to erythroid failure, is hypothesized to be the underlying defect. The genes identified to date that are mutated in DBA all encode ribosomal proteins associated with either the small or large subunit and in these cases haploinsufficiency gives rise to the disease. Extraordinarily robust laboratory and clinical investigations have recently led to demonstrable improvements in clinical care for patients with DBA.

Fig. 1. Hypothetic model for abortive ribosome assembly and p53 activation relevant to DBA

Panel A, 60S subunit assembly in healthy individuals; panel B, DBA patients haploinsufficient for RPL35A; panel C, DBA patients haploinsufficient for RPL5. Ribosomal RNAs are shown with twisted lines and ribosomal proteins are shown with circles. Relevant ribosomal proteins are indicted with their numerical designation in the center. The effects of ribosomal proteins on the level or activity of MDM2 and p53 are shown below the assembly pathways. The solid bars indicate that the 5S rRNA-Rpl5-Rpl11 ternary complex may bind more strongly to MDM2, and have a more substantial effect on p53 stabilization that Rpl11 alone (shown with dashed bars).

Fig. 2

Patient with Diamond Blackfan anemia originally diagnosed with Treacher Collins syndrome. Note absent lower eyelashes, down slanting palpebral fissures, deformed external ears, malar hypoplasia, and micrognathia.

Fig. 3. Proposed mechanism for cancer predisposition in Diamond Blackfan anemia

Ribosomal protein haploinsufficiency results in the accumulation of partially assembly intermediates that result in nucleolar stress signaling. Nucleolar stress, in turn, leads to p53 activation and either cell cycle arrest or apoptosis. These steps are outlined in red. Interdicting mutations that subvert the p53 pathway and favor the outgrowth of malignant clones are shown in green. Also shown in green are interdicting mutations that could enhance ribosomal protein synthesis and diminish nucleolar stress but because of the oncogenic nature of the genes involved could again favor the outgrowth of malignant clones.

Fig. 4. Putative biochemical function for Treacle, Dyskerin, Rps19/Rps24, RMRP, and Sbds in ribosomal biogenesis

A simplified version of the human pre-rRNA processing pathway is shown. Functions are deduced from data for either yeast or human orthologs. Mature rRNA species (denoted in bold) are liberated from the 45S pre-rRNA primary transcript by a series of processing steps. 5′ and 3′ ETS represent external transcribed sequences found on the 5′ and 3′ ends of the primary transcript, respectively. ITS represents internal transcribed sequences present in the primary transcript that are not retained in mature rRNAs. The 18S rRNA is a component of the 40S ribosomal subunit. The 5.8S and 28S rRNAs, together with the 5S rRNA (not shown), are components of the 60S ribosomal subunit.