scholarly journals Diamond-Blackfan anemia

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 353-360
Author(s):  
Lydie M. Da Costa ◽  
Isabelle Marie ◽  
Thierry M. Leblanc
Keyword(s):  
Bone Marrow ◽  
Developmental Stages ◽  
Bone Marrow Failure ◽  
Treatment Options ◽  
Heterozygous Mutation ◽  
Ribosomal Protein Genes ◽  
Bone Marrow Failure Syndrome ◽  
Diamond Blackfan Anemia ◽  
Increased Risk ◽  
Rrna Maturation

Abstract Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome, characterized as a rare congenital bone marrow erythroid hypoplasia (OMIM#105650). Erythroid defect in DBA results in erythroblastopenia in bone marrow as a consequence of maturation blockade between the burst forming unit–erythroid and colony forming unit–erythroid developmental stages, leading to moderate to severe usually macrocytic aregenerative (<20 × 109/L of reticulocytes) anemia. Congenital malformations localized mostly in the cephalic area and in the extremities (thumbs), as well as short stature and cardiac and urogenital tract abnormalities, are a feature of 50% of the DBA-affected patients. A significant increased risk for malignancy has been reported. DBA is due to a defect in the ribosomal RNA (rRNA) maturation as a consequence of a heterozygous mutation in 1 of the 20 ribosomal protein genes. Besides classical DBA, some DBA-like diseases have been identified. The relation between the defect in rRNA maturation and the erythroid defect in DBA has yet to be fully defined. However, recent studies have identified a role for GATA1 either due to a specific defect in its translation or due to its defective regulation by its chaperone HSP70. In addition, excess free heme-induced reactive oxygen species and apoptosis have been implicated in the DBA erythroid phenotype. Current treatment options are either regular transfusions with appropriate iron chelation or treatment with corticosteroids starting at 1 year of age. The only curative treatment for the anemia of DBA to date is bone marrow transplantation. Use of gene therapy as a therapeutic strategy is currently being explored.

Ribosomal Protein Genes S10 and S26 Are Commonly Mutated in Diamond-Blackfan Anemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 175-175 ◽  
Author(s):  
Hanna T. Gazda ◽  
Mee Rie Sheen ◽  
Leana Doherty ◽  
Adrianna Vlachos ◽  
Valerie Choesmel ◽  
...  
Keyword(s):  
Ribosomal Protein ◽  
Large Scale ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Ribosomal Protein Genes ◽  
Variants Of Unknown Significance ◽  
Diamond Blackfan Anemia ◽  
Increased Risk ◽  
Unknown Significance ◽  
Risk Of Cancer

Abstract Abstract 175 Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by anemia usually presenting during infancy or in early childhood, birth defects, and increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart and urinary system defects, that are present in ∼30–50% of patients. To date, DBA has been associated with mutations in seven ribosomal protein (RP) genes, S19, S24, S17, L35A, L5, L11, and S7 in about ∼43% of patients. To complete our large scale screen of RP genes in a DBA population, we sequenced 49 ribosomal protein genes in our DBA patient cohort of 117 probands. Together with our previous efforts of screening 29 RP genes, this completes the analysis of all known RP genes (excluding RPS4Y on the Y chromosome). Here we report probable mutations in four more RP genes, RPS10, RPS26, RPL19, and RPL26, and variants of unknown significance in six more, RPL9, RPL14, RPL23A, RPL7, RPL35, and RPL3. RPS10 and RPS26 are now confirmed DBA genes as we identified five mutations in RPS10 in five probands and nine mutations in RPS26 in 12 probands. We found single small frameshifting deletions in RPL19 and RPL26 in single DBA families. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knock-down of RPS10 or RPS26 expression with siRNAs, which indicate that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins. This brings to 11, the total number of RP genes mutated in ∼54% of patients with DBA, with nine more genes harboring variants of unknown significance requiring further study. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Acquired ribosomopathies in leukemia and solid tumors

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 716-719 ◽  
Author(s):  
Adrianna Vlachos
Keyword(s):  
Bone Marrow ◽  
Ribosomal Protein ◽  
Solid Tumors ◽  
Ribosomal Proteins ◽  
Bone Marrow Failure ◽  
Ribosomal Protein Gene ◽  
Small Subunit ◽  
Gene Encoding ◽  
Bone Marrow Failure Syndrome ◽  
Diamond Blackfan Anemia

AbstractA mutation in the gene encoding the small subunit-associated ribosomal protein RPS19, leading to RPS19 haploinsufficiency, is one of the ribosomal protein gene defects responsible for the rare inherited bone marrow failure syndrome Diamond Blackfan anemia (DBA). Additional inherited and acquired defects in ribosomal proteins (RPs) continue to be identified and are the basis for a new class of diseases called the ribosomopathies. Acquired RPS14 haploinsufficiency has been found to be causative of the bone marrow failure found in 5q– myelodysplastic syndromes. Both under- and overexpression of RPs have also been implicated in several malignancies. This review will describe the somatic ribosomopathies that have been found to be associated with a variety of solid tumors as well as leukemia and will review cancers in which over- or underexpression of these proteins seem to be associated with outcome.

scholarly journals Zebrafish Models of Diamond-Blackfan Anemia: A Tool for Understanding the Disease Pathogenesis and Drug Discovery

2019 ◽  
Vol 12 (4) ◽  
pp. 151 ◽  
Author(s):  
Tamayo Uechi ◽  
Naoya Kenmochi
Keyword(s):  
Drug Discovery ◽  
Danio Rerio ◽  
Bone Marrow Failure ◽  
Rapid Development ◽  
Disease Model ◽  
Ribosomal Protein Genes ◽  
Bone Marrow Failure Syndrome ◽  
Novel Treatments ◽  
Diamond Blackfan Anemia ◽  
Disease Mechanisms

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome characterized by red blood cell aplasia. Currently, mutations in 19 ribosomal protein genes have been identified in patients. However, the pathogenic mechanism of DBA remains unknown. Recently, several DBA models were generated in zebrafish (Danio rerio) to elucidate the molecular pathogenesis of disease and to explore novel treatments. Zebrafish have strong advantages in drug discovery due to their rapid development and transparency during embryogenesis and their applicability to chemical screens. Together with mice, zebrafish have now become a powerful tool for studying disease mechanisms and drug discovery. In this review, we introduce recent advances in DBA drug development and discuss the usefulness of zebrafish as a disease model.

Both p53-Dependent and -Independent Pathways Contribute to Erythroid Dysplasia in a Zebrafish Model for Diamond Blackfan Anemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 177-177 ◽  
Author(s):  
Elspeth Payne ◽  
Hong Sun ◽  
Barry H. Paw ◽  
A. Thomas Look ◽  
Arati Khanna-Gupta
Keyword(s):  
Bone Marrow ◽  
Ribosomal Protein ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Ribosomal Subunit ◽  
Specific Effect ◽  
Independent Component ◽  
Diamond Blackfan Anemia ◽  
Increased Risk ◽  
Erythroid Maturation

Abstract Abstract 177 Diamond Blackfan Anemia (DBA) is a congenital autosomal dominant bone marrow failure syndrome of childhood manifested as profound anemia. The disease is characterized by enhanced sensitivity of hematopoietic progenitors to apoptosis with evidence of stressed erythropoiesis. In addition to bone marrow defects, DBA patients often have craniofacial, genitourinary, cardiac and limb abnormalities and have an increased risk of developing hematopoietic malignancies and osteosarcoma. Twenty-five percent of patients with DBA have heterozygous mutations in the ribosomal protein S19 (RPS19) gene, which encodes a component of the 40S ribosomal subunit. Additionally, a growing percentage of DBA patients lacking a mutation in the RPS19 gene have been shown to have mutations in other ribosomal protein genes. These observations support the hypothesis that DBA is a disease of altered ribosome assembly and function. It is unclear how defects in ribosomal proteins have such a specific effect on erythroid maturation and cause increased apoptosis in the erythroid compartment. An attempt to model DBA by homozygous deletion of the Rps19 gene in mice proved to be embryonic lethal, and heterozygous mice appeared to fully compensate for the loss of one Rps19 allele, in contrast to the disease observed in humans. However, two groups have successfully modeled DBA in zebrafish using an antisense morpholino (MO) approach. These studies demonstrated that similar to the human disease, rps19 deficiency leads to defective erythropoiesis, increased apoptosis and to developmental abnormalities. A central role for the tumor suppressor p53 was suggested in one of these studies. It has previously been shown that any MO injection into zebrafish embryos can lead to the activation of the p53 pathway. Therefore, in order to clarify whether p53-independent effects also contributed to the DBA phenotype in zebrafish, we utilized the p53e7/e7 line that harbors a mutation within the p53 DNA-binding domain. Splice site and validated 5'UTR MOs targeting zebrafish rps19 were injected into one-cell stage embyros that were wildtype (WT) for p53 (AB) or mutated p53e7/e7. Staining for hemoglobin at 48 hours post fertilization showed a profound reduction in circulating blood in both p53 wild-type and p53 mutant embryos. Although p53 mutants injected with rps19 MO show a similar reduction in hemoglobin expression to WT morphants, they have a marked improvement in their developmental defects. A 20% decrease in expression of the transcription factor GATA-1 was observed in the rps19 morphants in the p53 mutant background compared to control MO injection. The implications of this finding are being further investigated and extended to include a panel of additional erythroid-specific factors. We have observed no increase in the levels of cell death, as measured by acridine orange (AO) staining or expression of the p53-regulated apoptosis associated gene PUMA, in the p53 mutant background. Taken together, our observations indicate that the phenotype observed in DBA has both a p53-dependent and a p53-independent component. We hypothesize that the p53-dependent component of DBA is likely responsible for the increased apoptosis associated with DBA while the erythroid maturation defect is associated, in large part, with a p53-independent component. Our studies are currently focused on identifying the players in the latter pathway. These investigations should shed light on thus far undefined pathways that will likely open new avenues for drug design and development for DBA. Disclosures: No relevant conflicts of interest to declare.

RAP-011 Efficiently Rescues Erythropoiesis In Zebrafish Models Of Diamond Blackfan Anemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3702-3702 ◽  
Author(s):  
Jason Ear ◽  
Haigen Huang ◽  
Zahra Tehrani ◽  
Victoria Sung ◽  
Thomas Daniel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Treatment Options ◽  
White Blood Cells ◽  
Independent Manner ◽  
Diamond Blackfan Anemia ◽  
Red Blood Cell Count ◽  
Equity Ownership ◽  
First Time ◽  
Potential Use

Abstract Diamond Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count but normal levels of platelets and white blood cells. Ribosomal mutations in RPS19, RPS26, RPL5, and RPL11 have been identified in approximately 50% of all DBA cases. Corticosteriod therapy and bone marrow transplantion are the most common treatment options for DBA patients. However, corticosteroids have severe side effects and bone marrow transplantation is risky; thus, novel therapeutics for DBA are needed. Sotatercept (ACE-011), an activin receptor IIA ligand trap which rapidly increased hemoglobin and hematocrit in both pharmacologic models and in healthy volunteers, is currently being evaluated in diseases of ineffective erythropoiesis such as ß-thalassemia and MDS. Non-clinical studies in mice have demonstrated that RAP-011, a murine ortholog of sotatercept, stimulates RBC parameters in mice through stimulating expansion of late-stage erythroblasts through a mechanism distinct from EPO. Here, we evaluated the effect of RAP-011 in zebrafish models of ribosome insufficiency in RPS19 and RPL11 that recapitulate the anemic phenotype seen in DBA patients. Treatment with RAP-011 treatment dramatically restored hemoglobin levels compromised by ribosome stress. Furthermore, the beneficial effect of RAP-011 is synergistic with corticosteriod treatment. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by altering the microenvironment of erythroid cells, reducing p21 levels through a p53-independent manner. These findings uncover a novel signaling pathway in the pathogenesis of DBA and support the potential use of Sotatercept for the treatment of DBA patients with ribosomal disorders. Our studies also demonstrate, for the first time, that protein drugs can be effectively evaluated in zebrafish human disease models, which offer a unique opportunity to identify the targets and study their mechanisms of action. Disclosures: Sung: Celgene Corp.: Employment. Daniel:Celgene: Employment. Chopra:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding.

scholarly journals Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry

Blood ◽  
2012 ◽  
Vol 119 (16) ◽  
pp. 3815-3819 ◽  
Author(s):  
Adrianna Vlachos ◽  
Philip S. Rosenberg ◽  
Eva Atsidaftos ◽  
Blanche P. Alter ◽  
Jeffrey M. Lipton
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Fanconi Anemia ◽  
Cancer Incidence ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Bone Marrow Failure Syndrome ◽  
Diamond Blackfan Anemia ◽  
Acute Myeloid

Abstract Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by red cell aplasia and congenital anomalies. A predisposition to cancer has been suggested but not quantified by case reports. The DBA Registry of North America (DBAR) is the largest established DBA patient cohort, with prospective follow-up since 1991. This report presents the first quantitative assessment of cancer incidence in DBA. Among 608 patients with 9458 person-years of follow-up, 15 solid tumors, 2 acute myeloid leukemias, and 2 cases of myelodysplastic syndrome were diagnosed at a median age of 41 years in patients who had not received a bone marrow transplant. Cancer incidence in DBA was significantly elevated. The observed-to- expected ratio for all cancers combined was 5.4 (P < .05); significant observed-to-expected ratios were 287 for myelodysplastic syndrome, 28 for acute myeloid leukemia, 36 for colon carcinoma, 33 for osteogenic sarcoma, and 12 for female genital cancers. The median survival was 56 years, and the cumulative incidence of solid tumor/leukemia was approximately 20% by age 46 years. As in Fanconi anemia and dyskeratosis congenita, DBA is both an inherited bone marrow failure syndrome and a cancer predisposition syndrome; cancer risks appear lower in DBA than in Fanconi anemia or dyskeratosis congenita. This trial was registered at www.clinicaltrials.gov as #NCT00106015.

scholarly journals Diamond-Blackfan anemia

Blood ◽  
2020 ◽  
Vol 136 (11) ◽  
pp. 1262-1273 ◽  
Author(s):  
Lydie Da Costa ◽  
Thierry Leblanc ◽  
Narla Mohandas
Keyword(s):  
Allelic Variation ◽  
Bone Marrow Failure ◽  
Ribosomal Subunit ◽  
Salient Feature ◽  
New Drugs ◽  
Ribosomal Protein Genes ◽  
Bone Marrow Failure Syndrome ◽  
Diamond Blackfan Anemia ◽  
Free Heme ◽  
Mechanistic Basis

Abstract Diamond-Blackfan anemia (DBA) was the first ribosomopathy described and is a constitutional inherited bone marrow failure syndrome. Erythroblastopenia is the major characteristic of the disease, which is a model for ribosomal diseases, related to a heterozygous allelic variation in 1 of the 20 ribosomal protein genes of either the small or large ribosomal subunit. The salient feature of classical DBA is a defect in ribosomal RNA maturation that generates nucleolar stress, leading to stabilization of p53 and activation of its targets, resulting in cell-cycle arrest and apoptosis. Although activation of p53 may not explain all aspects of DBA erythroid tropism, involvement of GATA1/HSP70 and globin/heme imbalance, with an excess of the toxic free heme leading to reactive oxygen species production, account for defective erythropoiesis in DBA. Despite significant progress in defining the molecular basis of DBA and increased understanding of the mechanistic basis for DBA pathophysiology, progress in developing new therapeutic options has been limited. However, recent advances in gene therapy, better outcomes with stem cell transplantation, and discoveries of putative new drugs through systematic drug screening using large chemical libraries provide hope for improvement.

scholarly journals Marrow Failure

Hematology ◽  
2002 ◽  
Vol 2002 (1) ◽  
pp. 58-72 ◽  
Author(s):  
Alan D. D’Andrea ◽  
Niklas Dahl ◽  
Eva C. Guinan ◽  
Akiko Shimamura
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Treatment Options ◽  
Clinical Manifestations ◽  
Molecular Pathogenesis ◽  
Diagnostic Assays ◽  
Diamond Blackfan Anemia ◽  
Bone Marrow Failure Syndromes ◽  
Wide Range

Abstract This chapter describes the clinical presentation and molecular basis of two inherited bone marrow failure syndromes, Fanconi anemia (FA), and Diamond-Blackfan anemia (DBA). It also provides an update on diagnostic and therapeutic approaches to bone marrow failure of all types (inherited and acquired) in pediatric patients. In Section I, Dr. Alan D’Andrea reviews the wide range of clinical manifestations of Fanconi anemia. Significant advances have been made in understanding the molecular pathogenesis of FA. On the basis of these advances, new diagnostic assays and treatment options are now available. In Section II, Dr. Niklas Dahl examines the clinical features and molecular pathogenesis of Diamond-Blackfan anemia. The possible links between the RPS19 gene (DBA gene) and the erythropoiesis defect are considered. In Section III, Drs. Eva Guinan and Akiko Shimamura provide an algorithm for the diagnostic evaluation and treatment of children with inherited or acquired aplastic anemia. Through the presentation of a case study of a pediatric patient with bone marrow failure, he provides an overview of the newest tests and treatment options.

scholarly journals Post Allograft Rituximab Responsive Cytopenia (RRC)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5645-5645
Author(s):  
Samar Kulkarni ◽  
John Murray ◽  
David Kaye ◽  
Michael Dennis ◽  
Anna Castleton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Response Rate ◽  
Bone Marrow Failure ◽  
Treatment Options ◽  
Complete Response ◽  
Electronic Patient Records ◽  
Bone Marrow Failure Syndrome ◽  
Post Transplant ◽  
Educational Grant ◽  
Immune Mediated

Background: Cytopenia post allograft can be multi-factorial. Known causes include viral infection, septicaemia, graft versus host disease (GVHD), nutritional deficiency, myelotoxic drugs, relapsed malignancy but immune mediated cases are increasingly observed. There remains a group of cases where no obvious cause is identified. The incidence of this complication is small but may be underestimated and treatment options and results are not defined. Aim: This single centre analysis retrospectively evaluated cases of post-transplant cytopenia presumed to be immune mediated or with no obvious cause and response to antiCD20 antibody (Rituximab) therapy. Study period was 2012 to 2019. Data was collected from electronic patient records, case notes and haematology data base. Results: From 2012 to 2019, 988 patients received allograft (n=390) or autograft (n=598) for haematological malignancy or bone marrow failure syndrome. Twenty-four cases received Rituximab for cytopenia post allograft (24/390, 6.2%). Median age was £9yr. (range: 19-68), 19 were males (79.2%) and allograft were done for severe aplastic anaemia (n=4), Ac. Leukaemia (n=6), Hodgkins disease (n=4), non-Hodgkins lymphoma (n=4), MPD/MDS (n=5) and myeloma (n=1). Conditioning was reduced intensity in n22 case, myeloablative in 2 cases and included campath (n=18) or ATG (n=2) in 20 cases (83.3%). Donor was sibling (n=6) or unrelated (n=22) and 23 (96%) patients received PBSC. All allografts were donor/patient CMV matched (NN: 15, PP: 9). Rituximab was used at a median of 171 days post transplant (range: 55-6174). Cytopenia was trilineage in 8, bilineage in 10 and single lineage in 6 cases. Median haematological parameters were as follows: Hb 78gm/L (68-152), WBC: 2x109/L (0-12), Platelets 28x109/L (4-638). DCT was positive in 7 of the 15 cases where results were available. Seventeen of the 22 cases who had bone marrow evaluation showed hypocellular marrow with no malignancy (3 had normocellular marrow) . Seven of the 10 cases where reticulocyte count pre-rituximab was available, showed response above 2% . Cytopenia was not related to infection, viruses, it B12 or folate deficiency. Response to rituximab therapy was defined as CR (normal counts, transfusion independence, no treatment with steroids or G-CSF), Stable (improvement in counts with platelets>50, Hb>100 and ANC>1.0 without support) or no response. Rituximab was delivered weekly in the dose of 375mg/m2 for 4 weeks. Twelve patients achieved complete response (50%), 3 achieved stabilization (12.5%) and 9 did not show any response (37%) for overall response rate of 63%. All patients with positive DCT responded to Rituximab (7/7, 100%) but even in negative DCT group 4 responded (4/8, 50%). Response was 100% in single lineage cytopenia (6/6), 40% in bilineage cytopenia (4/10) and 63% in trilineage cytopenia (5/8) [p=0.052]. Three patients received second course of Rituximab for recurrence of cytopenia and all achieved second complete response (all three had autoimmune haemolysis). Numbers are too small to identify the predictors but there was trend towards better outcome in patients younger than 40 yrs. age (10/12 vs. 5/12, p=0.035) and patients with Hodgkins disease (4/4 vs. 11/20, p=0.09) but there was no effect of gender, intensity of conditioning, use of campath/ATG or CMV status. Treatment was well tolerated and infusion reactions were uncommon. We identify that the main drawback of this analysis is substantial amount of missing data, especially haematological investigations that precludes identification of predictors or trends. Conclusion: Rituximab should be considered as an option for management of post allograft cytopenia with immune aetiology or with no identified cause. Response rate is substantial and the benefit is sustained. It will be useful to have larger cohort of cases to identify the predictors of response. Disclosures Kulkarni: Therakos, Clegene: Honoraria. Murray:Therakos: Honoraria. Castleton:Novartis, Pfizer, Amgen: Consultancy, Honoraria. Cavet:AMGEN, Autolus, Celgene, EUSA, Jansen/J&J, Novartis,: Consultancy, Honoraria, Research Funding, Speakers Bureau. Wiseman:Novartis, Celgene: Consultancy, Honoraria. Somervaille:Novartis: Consultancy. Sommerfeld:Gilead: Other: Educational grant. Bloor:Abvie, Gilead, Novartis, Autolus, Celgene, etc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational grant.

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