Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer

Ebert, Benjamin L.

doi:10.1038/leu.2009.53

Cited by 88 publications

(80 citation statements)

References 61 publications

(72 reference statements)

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“…33 For example, haploinsufficiency for miR-145 and miR-146a may contribute to thrombocytosis, and haploinsufficiency for EGR1 may contribute to the clonal advantage of the del(5q) clone. [36][37][38][39] Nevertheless, in vitro and in vivo studies indicate that the erythroid defect, the aspect of the 5qϪ syndrome phenotype most analogous to DBA, is caused by RPS14 haploinsufficiency.…”

Section: Q؊ Syndromementioning

confidence: 99%

“…[28][29][30][31][32] RPS14 was identified as a 5qϪ syndrome gene in an RNA interference screen of each gene within the 5qϪ syndrome common deleted region. 3,33 In patients with the 5qϪ syndrome, 1 allele of RPS14 is deleted, 3 and haploinsufficient expression of RPS14 has been confirmed in patient samples. 3,34 Decreased expression of RPS14 causes impaired erythropoiesis, with relative preservation of the other lineages.…”

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confidence: 99%

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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: Q؊ Syndromementioning

confidence: 99%

mentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

689

726

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“…Of note, no significant differences in break points were observed between patients with the '5qÀsyndrome' and the rest of the series, in contrast with which was previously reported. 27 Karyotype complexity is a well-known prognostic factor in MDS. 5,8,10,11,28,29 However, in MDS patients with deletion 5q prognostic value of the number of chromosomal abnormalities in addition to deletion 5q (for example, complexity of the karyotype) is still a matter of debate, with previous reports showing conflicting results.…”

Section: Discussionmentioning

confidence: 99%

Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q

Cervera²,

et al. 2010

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This cooperative study assessed prognostic factors for overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in 541 patients with de novo myelodysplastic syndrome (MDS) and deletion 5q. Additional chromosomal abnormalities were strongly related to different patients' characteristics. In multivariate analysis, the most important predictors of both OS and AML transformation risk were number of chromosomal abnormalities (Po0.001 for both outcomes), platelet count (Po0.001 and P ¼ 0.001, respectively) and proportion of bone marrow blasts (Po0.001 and P ¼ 0.016, respectively). The number of chromosomal abnormalities defined three risk categories for AML transformation (del(5q), del(5q) þ 1 and del(5q) þ X2 abnormalities) and two for OS (one group: del(5q) and del(5q) þ 1; and del(5q) þ X2 abnormalities, as the other one); with a median survival time of 58.0 and 6.8 months, respectively. Platelet count (P ¼ 0.001) and age (P ¼ 0.034) predicted OS in patients with '5qÀsyndrome'. This study demonstrates the importance of additional chromosomal abnormalities in MDS patients with deletion 5q, challenges the current '5qÀsyndrome' definition and constitutes a useful reference series to properly analyze the results of clinical trials in these patients.

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“…3,4 For over 15 years, many studies have focused on defining the common deleted region of chromosome 5.…”

mentioning

confidence: 99%

Molecular characterization of deletions of the long arm of chromosome 5 (del(5q)) in 94 MDS/AML patients

et al. 2012

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Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer

Cited by 88 publications

References 61 publications

Ribosomopathies: human disorders of ribosome dysfunction

Ribosomopathies: human disorders of ribosome dysfunction

Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q

Molecular characterization of deletions of the long arm of chromosome 5 (del(5q)) in 94 MDS/AML patients

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