Distinct haematological disorder with deletion of long arm of No. 5 chromosome

Berghe, Herman Van den; Cassiman, Jean‐Jacques; Gourichon, David; Fryns, Jean‐Pierre; Michaux, Jean‐Louis; Sokal, G.

doi:10.1038/251437a0

Cited by 419 publications

(168 citation statements)

References 2 publications

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“…26 Patients with the 5qϪ syndrome, an independent subtype of myelodysplastic syndrome (MDS) in the World Health Organization classification system in which del(5q) is the sole cytogenetic abnormality, characteristically have a severe macrocytic anemia, normal/elevated platelets with hypolobulated micromegakaryocytes, and a relatively low rate of progression to acute myeloid leukemia (AML) compared with other types of MDS. 27 Lenalidomide, a derivative of the immunomodulatory agent thalidomide, is highly effective for patients with the 5qϪ syndrome.…”

Section: Q؊ Syndromementioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

688

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%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

688

726

View full text Add to dashboard Cite

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“…The 5qÀ syndrome was reported in 1974 by Van den Berghe et al 8 as the first hematologic disorder associated with a specific chromosomal deletion. The clinical features have been refined in larger patient series, and the World Health Organization classification of MDS now recognizes the 5qÀ syndrome as a distinct entity, the only subtype defined by a molecular abnormality (Table 1).…”

Section: Introductionmentioning

confidence: 99%

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

Ebert

2009

Leukemia

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“…10 Patients with the 5qÀ syndrome, in which the del(5q) is the sole karyotypic abnormality, are characterized by a macrocytosis, anemia, normal or high platelet count and hypolobulated megakaryocytes in the bone marrow and a good prognosis. [11][12][13] The presence of À7/del(7q) is associated with a frequent progression to AML, and chromosome 7 abnormalities are an indicator of a poor prognosis in the International Prognostic Scoring System. 8 In comparison, MDS with trisomy 8 typically has an intermediate prognosis; 8 peripheral blood cytopenias are often responsive to immunosuppressive treatment, 14 and have a more favorable prognosis.…”

Section: Introductionmentioning

confidence: 99%

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

et al. 2010

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To gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathways. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or À7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with À7/del(7q) by pathways involved in cell survival, whereas patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder, thereby providing new targets for therapeutic intervention.

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Distinct haematological disorder with deletion of long arm of No. 5 chromosome

Cited by 419 publications

References 2 publications

Ribosomopathies: human disorders of ribosome dysfunction

Ribosomopathies: human disorders of ribosome dysfunction

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

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

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