Van‐den Berghe’s 5q‐ syndrome in 2008

Abstract

Summary Van Den Berghe established 5q‐ syndrome as a discrete clinical entity in 1974 when he described patients with macrocytic anaemia, thrombocytosis, dyserythropoiesis, hypolobulated megakaryocytes and an interstitial deletion within chromosome 5q. With del(5q) as the sole cytogenetic abnormality, 5q‐ syndrome represents an opportunity to define precisely the molecular defect(s) underlying the pathogenesis of this disease. The commonly deleted region in 5q‐ syndrome, which is distinct from that in patients with complex cytogenetic changes that include del(5q), includes the ribosomal protein S14 locus and it has been proposed that that loss of an RPS14 allele accounts for the 5q‐ syndrome phenotype. However, this hypothesis fails to explain the growth advantage of the 5q‐ syndrome clone and it is evident that ribosomal protein defects are not specific to 5q‐ syndrome, as they are found in other bone marrow failure syndromes. Lenalidomide therapy leads to normalization of both haematological and cytogenetic parameters in the majority of 5q‐ syndrome patients. This review examines the potential role of several genes, including RPS14, in the pathogenesis of the 5q‐ syndrome and recent advances in clinical management, with particular emphasis on the role and mechanism of action of lenalidomide.

Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion

“…[13][14][15][16][17][18][19]38 Although lenalidomide seems to target mainly BM microenvironment structures, the drug has been described to have a direct effect on clonal hematopoietic cells through inhibition of proteins critical for cell survival or stimulation of tumor suppressor genes in the 5q region. 10,39 Many mechanisms of action of lenalidomide on patients' hematopoiesis do, however, remain undefined.…”

“…Specifically, it has been shown that treatment with lenalidomide decreases BM microvessel density, indicating an anti-angiogenic activity which has been associated with a reduction in the levels of pro-angiogenic cytokines 7,10,43 It has also been shown that lenalidomide may decrease the production of pro-inflammatory mediators in the BM microenvironment and may alter cell-to-cell interactions through modification of expression of adhesion molecules and stimulation of responses of cytotoxic T and NK cells. 39 To probe the effect of lenalidomide on the hematopoiesis-supporting potential of BM stroma, we used the LTBMC system which has long been considered as a representative in vitro model mimicking the BM microenvironment. 35 We observed a substantial improvement in the capacity of the adherent layers of patients' LTBMC to sustain autologous and normal hematopoietic progenitor cell growth following lenalidomide treatment.…”

Myelodysplastic syndromes: an update on molecular pathology

“…These observations suggest that defective erythropoiesis in the 5q-syndrome is caused by a defect in ribosomal protein function. Accordingly, RPS14 has been identiÞ ed as the most likely candidate for the 5q-syndrome phenotype [60]. The similarity of the genetic mechanism between 5q-syndrome and other congenital bone marrow disorders such as Diamond-Blackfan anaemia, congenital dyskeratosis and Shwachman-Diamond syndrome is remarkable, and has generated the concept of ribosomopathies as human disorders of ribosome dysfunction [61] (Fig.…”

The 5q- Syndrome: Biology and Treatment

“…In practice, prognostic tools aim to stratify patients into lower and higher risk sub-groups. Patients with the 5q-syndrome, by definition, always fall into the lower risk sub-group and therefore treatment has remained supportive [3,58]. Historically, patients with the 5q-syndrome developed transfusion dependent anemia, which over time led to the development of iron overload.…”

“…Erythroid hypoplasia is accompanied by characteristic megakaryocytic dysplasia with small oligo-or mononuclear forms, and less than 5% myeloblasts in the bone marrow biopsy and aspirate [2]. The clinical presentation includes transfusion-dependent anemia, female predominance (7:3), and a low propensity to transform to acute myeloid leukemia (AML) [3,4]. A commonly deleted interstitial segment on chromosome five is the defining cytogenetic feature of the disease [5,6].…”