Hematopoietic stem cell transplantation for Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry

Vlachos, Adrianna; Federman, Noah; Reyes-Haley, C; Abramson, Jeremy S.; Jm, Lipton

doi:10.1038/sj.bmt.1702784

Cited by 85 publications

(64 citation statements)

References 27 publications

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“…9 Current therapies include steroids and chronic transfusions, with the only definitive treatment being bone marrow transplantation. 15 Since the initial description in 1999 by Draptchinskaia, mutations in RPS19, RPS24, RPS17, and RPL35A have been identified in approximately one-third of patients with DBA. [16][17][18][19] More recently, Gazda et al identified mutations in RPL5 and RPL11 in an additional 11.4% of patients and noted that mutations in RPL5 were associated with a higher frequency of physical abnormalities, including cleft lip and/or palate, whereas mutations in RPL11 had more isolated thumb abnormalities compared with patients with mutations in RPS19.…”

Section: Diamond-blackfan Anemiamentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

689

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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Section: Diamond-blackfan Anemiamentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

689

726

View full text Add to dashboard Cite

show abstract

“…[1][2][3] Current therapies such as steroids, blood transfusion, and bone marrow transplantation often have severe side effects or are ineffective in many DBA patients. 1,[4][5][6][7][8] Approximately 40% of DBA patients have additional abnormalities that include short stature, cranofacial and urogenital malformations, heart defects and mental retardation. 1,8 DBA patients are also predisposed to develop acute myeloid leukemia, lymphoma and solid tumors.…”

Section: Introductionmentioning

confidence: 99%