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Bezzerri, V.; Api, M.; Allegri, M.; Fabrizzi, B.; Corey, S.J.; Cipolli, M. Inherited Bone Marrow Failure Syndromes. Encyclopedia. Available online: (accessed on 20 June 2024).
Bezzerri V, Api M, Allegri M, Fabrizzi B, Corey SJ, Cipolli M. Inherited Bone Marrow Failure Syndromes. Encyclopedia. Available at: Accessed June 20, 2024.
Bezzerri, Valentino, Martina Api, Marisole Allegri, Benedetta Fabrizzi, Seth J. Corey, Marco Cipolli. "Inherited Bone Marrow Failure Syndromes" Encyclopedia, (accessed June 20, 2024).
Bezzerri, V., Api, M., Allegri, M., Fabrizzi, B., Corey, S.J., & Cipolli, M. (2020, July 03). Inherited Bone Marrow Failure Syndromes. In Encyclopedia.
Bezzerri, Valentino, et al. "Inherited Bone Marrow Failure Syndromes." Encyclopedia. Web. 03 July, 2020.
Inherited Bone Marrow Failure Syndromes

Inherited bone marrow failure syndromes (IBMFS) are a group of cancer prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. Unofrtunately, no pharmacological therapies have been developed for IBMFS so far and bone marrow hematopoietic stem cell transplant remains the unique option to correct bone marrow failure and prevent myeloid neoplasia.

bone marrow nonsense mutations rare diseases ataluren Fanconi Anemia Dyskeratosis Congenita Diamond-Blackfan Anemia Shwachman-Diamond Syndrome Severe Congenital Neutropenia

1. Introduction

Inherited bone marrow failure syndromes (IBMFS) are cancer prone disorders characterized by peripheral cytopenia(s) with a hypocellular bone marrow and impairment in one or more hematopoietic lineages. The classical IBMFS are represented by Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). Importantly, 10–15% of bone marrow aplasia and 30% of pediatric bone marrow failure disorders are caused by IBMFS, with approximately 65 cases per million live births every year [1]. However, emerging data reveal that IBMFS are underdiagnosed because of decreased recognition or because genetic mutation associated with congenital bone marrow failure are detected only after a malignancy has arisen [2].

Clinical management of IBMFS requires multidisciplinary care and surveillance to detect early emergence of malignancies. Early hematopoietic stem cell transplant (HCT) may correct bone marrow failure and prevent the development of myeloid neoplasia, but it does not affect the risk of solid tumors. However, post-HCT complications, such as graft-versus-host disease and immune dysfunction, frequently occur. As an alternative to HCT, androgen administration may be suitable for patients with FA and DC. Corticosteroids are often effective for patients with DBA, especially for those who lack a compatible donor or are ineligible for HCT transplantation. In addition, recombinant granulocyte colony-stimulating factor (G-CSF) is used to ameliorate severe neutropenia in SCN or SDS and prevent recurrent infections. Long-term use of G-CSF in SCN and SDS has been associated with increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [3]. No therapies to reduce bone marrow failure or cancer risk in IBMFS have been developed so far.

It has been estimated that approximately 12% of human genetic disorders are caused by single-nucleotide or out-of-frame nonsense mutations, leading to the generation of premature termination codons (PTC). Correct protein synthesis normally represents the core of biological process for any living organism. For this reason, protein synthesis is regulated at multiple levels and any disruption on each of these steps may cause severe diseases. The therapeutic strategy aimed at overcoming PTC has been defined as “nonsense suppression therapy”. This approach is intended to generate the readthrough of PTC, restoring a full-length protein synthesis. Alternatively, nonsense suppression therapy may be designed to reduce the nonsense mediated decay (NMD) induced by the nonsense mutations. NMD is an evolutionarily conserved defense mechanism of eukaryotic cells that surveys newly synthesized mRNA and degrades transcripts containing a PTC [4][5].

Bezzerri and colleagues tested the efficacy of a small nonsense suppressor molecule, ataluren (PTC124, PTC Therapeutics, NJ) [6], in correcting the basic defect of SDS with promising preclinical results. That preclinical study might serve as proof of concept for the development of nonsense suppression therapy for other IBMFS. 

2. Development

2.1. Inherited Bone Marrow Failure Syndromes

Bone marrow failure syndromes (BMFS) cluster different disorders characterized by impaired hematopoiesis which lead to selective or global cytopenia. BMFS may be acquired, such as aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PHN), or congenital. IBMFS are classified into those that result in pancytopenia and those limited to deficiency of one or more hematopoietic lineages. FA and DC are characterized by progressive peripheral pancytopenia. Patients with DBA exhibit anemia, whereas SDS and SCN are mostly associated with severe neutropenia. Some of the IBMFS can be characterized by physical anomalies and failure to thrive. IBMFS are all associated with increased risk for the development of MDS/AML and solid tumors.

Approximately 80 different genes have been associated with different IBMFS [6]. Notably, 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC mutated alleles show nonsense pathogenic variants (Figure 1). Classes of genes correlate with specific IBMFS, such as genes which encode for proteins involved in DNA repair (FA), telomere biology (DC), and ribosome biogenesis (DBA). Many cancers have been associated with somatic mutations in genes encoding ribosomal proteins [7]. Importantly, defective ribosomal proteins may induce the upregulation of the tumor suppressor gene TP53 which encode the tumor suppressor protein p53 [8][9]. In this regard, p53 over-activation has been implicated in the pathogenesis of DBA, SDS, and DC [10][11][12].



Figure 1. Incidence of nonsense mutations in inherited bone marrow failure syndromes (IBMFS). Percentages have been calculated on the basis of ClinVar database [13]. Only pathogenic and likely pathogenic variants have been taken into account.

2.2. The Nonsense Suppression Therapy

The termination of eukaryotic translation process requires the recognition of a stop codon into the A (aminoacyl) site of ribosome by specific aminoacyl-tRNA bounded to eukaryotic translation termination factor 1 (eRF1) and GTP. Rarely, translational mistakes, defined as mispairing, could occur when a near-cognate aminoacyl-tRNA, whose anticodon is complementary just for two of the three nucleotides of a stop codon, improperly binds the stop codon. This process, defined “readthrough”, leads to the incorporation of an amino acid into the nascent polypeptide chain preventing the normal termination of translation. It has been estimated that the endogenous readthrough take place in 0.001% to 0.1% of total tranlsation processes and 0.01% to 1% generally occurs at the PTC [14][15][16]. It follows that PTC may be endogenously inhibited by the natural readthrough leading to a random substitution of the eRF1 with a near-cognate (nc)-tRNA [17][18]. Several factors can affect the readthrough process, including the sequence of nucleotides upstream and downstream the stop codon. It has been observed that the nucleotide which immediately follows the termination codon in the 3′ direction (position +4, considering the first nucleotide of stop codon as +1) is involved in the interactions between mRNA and the translational machinery [19][20][21]. For instance, studies conducted in yeasts have suggested that cytosine at position +4 negatively affect the recognition of eRF1 on the stop codon [22]. Additionally, nucleotides located at positions +5, +6 and +9 can influence the translational readthrough. The relative abundance of various near-cognate aminoacyl-tRNAs is another important aspect [23].

3. Discussion and Perspectives

No pharmacological therapies designed specifically against an IBMFS have been developed yet. The application of gene therapy and induced pluripotent stem cells (iPS) sounds promising. At least two lentiviral gene-based trials are recruiting for the treatment of Fanconi anemia (NCT01331018 and NCT03157804). In addition, gene editing has recently raised interest of IBMFS community. The correction of FANCAFANCCFANCD1/BRCA2FANCI, and FANCF pathogenic variants by CRISPR-Cas9 gene editing has been demonstrated in vitro [24][25][26][27]. Gene editing approach based on CRISPR/Cas9-sgRNA has also been recently shownto reduce ELANE expression ex vivo in bone marrow hematopoietic progenitors from patients with SCN. CRISPR-Cas9-mediated knockdown of ELANE significantly induced neutrophil maturation in vitro [28]. It should be nevertheless noted that CRISPR-Cas9 technology presents several limitations for its rapid translation as a therapy, including cell type dependent delivery, incomplete efficiency of homologous recombination and the possibility of off-target editing [29].

Because 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC mutated alleles (Figure 1) carry nonsense mutations in IBMFS-related genes, Bezzerri and colleagues proposed another approach, that of nonsense suppressor therapy. Nonsense suppression therapy used in non-hematologic genetic diseases such as DMD and CF. Ataluren (Translarna®) is an approved drug for the treatment of DMD and, importantly, several Phase II/III clinical studies reported very low toxicity of ataluren even in pediatric patients aged two and older [30][31][32][33][34][35][36].

Little is known about their effect on IBMFS. It has been already reported that ataluren improves SBDS full-length protein synthesis and function in bone marrow hematopoietic progenitors and mesenchymal stromal cells isolated from bone marrow biopsies of patients with SDS .

PTC-readthrough inducer molecules generally exhibit low efficiency. Although ataluren showed encouraging preclinical results in CF models, restoring CFTR protein synthesis and chloride function, the clinical development has been subsequently discontinued because of poor clinical benefits in terms of respiratory function improvement. A post hoc subgroup analysis demonstrated that a sub-cohort of patients treated with ataluren reported some clinical benefit. A recent clinical study showed that a partial synergistic effect of ivacaftor and ataluren can be observed in terms of improvement of nasal potential difference, although the major limitation of this study was the very little number (only two) of patients tested [32].

Ataluren however failed in a model of Dravet syndrome, an autosomal dominant form of epilepsy, perhaps because of codon selectivity. Its efficacy may depend on the sequence of PTC (UAA<UAG<UGA) [37][38]. Interestingly, both aniridia and SDS models, where ataluren significantly improved the target protein synthesis and function with promising in vivo and ex vivo results, shared the same stop codon, namely UGA, which is the hypothetical best sequence. Alternatively, readthrough efficacy may depend on the tissue and cell type targeted by the therapy [39]. Positive responses from blood cells derived from both aniridia and SDS justify the use of ataluren in other IBMFS.

Besides ataluren, several other readthrough inducer molecules have been synthesized and preclinically tested so far. Some ataluren analogues have shown increased in vitro efficacy compared to ataluren [40][41]. However, little is known about the toxicity of these molecules and further studies are needed to clarify this important step in drug development.

Another strategy aimed at restoring nonsense mutated transcripts is due by NMD inhibitors. However, as previously discussed, since the endogenous readthrough occurs very infrequently, a therapeutic approach aimed only at inhibiting the NMD, without increasing the readthrough capability, might not be sufficient for clinical purposes. One strategy would be to combine the two approaches to enhance full-length protein synthesis from transcripts of nonsense-mutated genes. For example, PTC-readthrough enhancers may potentiate the effect of reathrough-inducer drugs.

L-leucine administration improved the anemiain rps19-deficient zebrafish model of DBA by activating the mTOR pathway [42]. Moreover, L-leucine treatment has been proposed to activate translation of erythroid cells, improving globin gene synthesis and ameliorating the anemic phenotype in rps19 and rpl11 mutants in zebrafish [43]. These studies support a Phase I/II clinical trial (NCT01362595) that evaluates the effect of L-leucine supplementation on red blood cell transfusion dependent DBA patients. Since L-leucine may promote protein synthesis in erythroid cells, combinationtherapy of L-leucine, NMD inhibitors and/or PTC-readthrough inducers could improve the anemia of DBA.

All these premises suggest therefore that nonsense suppression therapy should be tested in IBMFS with hopeful expectations. Even if only preclinical positive results have been achieved so far, they should be considered as new important proof of concepts for extending the current therapeutic scenario for IBMFS.


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