Important Genes in the Pathogenesis of 5q- Syndrome and Their Connection with Ribosomal Stress and the Innate Immune System Pathway

Ota Fuchs

doi:10.1155/2012/179402

Abstract

Myelodysplastic syndrome (MDS) with interstitial deletion of a segment of the long arm of chromosome 5q [del(5q)] is characterized by bone marrow erythroid hyperplasia, atypical megakaryocytes, thrombocythemia, refractory anemia, and low risk of progression to acute myeloid leukemia (AML) compared with other types of MDS. The long arm of chromosome 5 contains two distinct commonly deleted regions (CDRs). The more distal CDR lies in 5q33.1 and contains 40 protein-coding genes and genes coding microRNAs (miR-143, miR-145). In 5q-syndrome one allele is deleted that accounts for haploinsufficiency of these genes. The mechanism of erythroid failure appears to involve the decreased expression of the ribosomal protein S14 (RPS14) gene and the upregulation of the p53 pathway by ribosomal stress. Friend leukemia virus integration 1 (Fli1) is one of the target genes of miR145. Increased Fli1 expression enables effective megakaryopoiesis in 5q-syndrome.

Highlights

15% of patients with Myelodysplastic syndrome (MDS) have abnormalities of chromosome 5 [1]
15% of patients with MDS have abnormalities of chromosome 5 [1]. These abnormalities include interstitial deletion of a segment of the long arm of chromosome 5q [del(5q), 5q-syndrome], monosomy, and unbalanced translocations. 5q-syndrome as MDS category was defined by the World Health Organization (WHO) [2], and it is characterized by refractory macrocytic anemia with dyserythropoiesis, transfusion dependence, normal to elevated platelet counts, hypolobated and nonlobated megakaryocytes, female preponderance, a favourable prognosis, and low risk of progression to acute myeloid leukemia (AML) compared with other types of MDS [3,4,5,6,7,8,9,10]
We studied the role of the levels of mRNA for transcriptions factors Fli-1 (Friend leukemia virus integration 1) and EKLF in mononuclear cells isolated from bone marrow and peripheral blood of MDS patients with 5q-syndrome in comparison with patients with low risk MDS without 5q chromosome abnormality and with healthy controls [124, 125]

Summary

Introduction

15% of patients with MDS have abnormalities of chromosome 5 [1]. These abnormalities include interstitial deletion of a segment of the long arm of chromosome 5q [del(5q), 5q-syndrome], monosomy, and unbalanced translocations. 5q-syndrome as MDS category was defined by the World Health Organization (WHO) [2], and it is characterized by refractory macrocytic anemia with dyserythropoiesis, transfusion dependence, normal to elevated platelet counts, hypolobated and nonlobated megakaryocytes, female preponderance, a favourable prognosis, and low risk of progression to AML compared with other types of MDS [3,4,5,6,7,8,9,10]. Boultwood et al [15] characterised the commonly deleted region (CDR) in a study involving sixteen 5q-syndrome patients to a 1.5 Mb interval located at 5q32-5q33 between D5S413 marker and GLRA1 (glycine receptor subunit α-1). This region contains PDE6A (phosphodiesterase 6A), CSF1R, CD74 (CD74/cluster of differentiation 74/molecule, major histocompatibility complex, class II invariant chain), TCOF1 (Treacher-Collins-Franceschetti syndrome 1), ANXA6 (annexin A6), SPARC, and FAT2 (FAT tummor suppressor homolog 2, known as cadherin family member 8 or multiple epidermal growth factor-like domains protein 1) genes. MDia acts as a node in a tumor-suppressor network that involves multiple 5q gene products

The Possible Role of Candidate Genes from CDR in 5q-Syndrome

The Role of miR-145 and miR-146a in the 5q-Syndrome

The Importance of p53 in the Molecular Mechanism of 5q-Syndrome

Role of Further Genes in 5q-Syndrome

Findings

Conclusions and Perspectives