Biomedical subjects

Andrea Pellagatti

Publications and source records attributed to Andrea Pellagatti.

6 recordsLinked to original sources

PubMed2006

Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype.

To gain insight into the poorly understood pathophysiology of the myelodysplastic syndromes (MDSs), we have determined the gene expression profiles of the CD34+ cells of 55 patients with MDS by using a comprehensive array platform. These profiles showed many similarities to reported interferon-gamma-induced gene expression in normal CD34+ cells; indeed the 2 most up-regulated genes, IFIT1 and IFITM1, are interferon-stimulated genes (ISGs). Alterations in the expression of ISGs may play a role in the hematologic features of MDS, such as peripheral blood cytopenias. Up-regulation of IFIT1 is a potential diagnostic marker for MDS. We determined whether distinct gene expression profiles were associated with specific FAB and cytogenetic groups. CD34+ cells from patients with refractory anemia with ringed sideroblasts (RARS) showed a particular gene expression profile characterized by up-regulation of mitochondrial-related genes and, in particular, of those of heme synthesis (eg, ALAS2). CD34+ cells from patients with the del(5q) had a distinct gene expression profile, characterized by down-regulation of genes assigned to 5q, and up-regulation of the histone HIST1 gene cluster at chromosome 6p21 and of genes related to the actin cytoskeleton. This study provides important and new insights into the pathophysiology of MDS.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Gene expression profiling in the myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a heterogeneous group of haematopoietic malignancies, characterized by blood cytopenias, ineffective hematopoiesis and hypercellular bone marrow. Several genetic alterations have been reported in MDS but these are not MDS-specific and the underlying molecular causes of the disease remain poorly understood. Gene expression microarray technology allows the simultaneous parallel analysis of many thousands of genes and has already provided novel insights into cancer pathogenesis. In this review we discuss the results of several recent studies which utilize the enormous power of microarray technology for the study of MDS. Several exciting findings have emerged from these early studies that highlight the potential of this technology to further our understanding of the molecular pathogenesis of this disorder. It is clear, however, that these findings should be confirmed in larger sets of MDS patients.

Bone Marrow↗

PubMed2004

Gene expression profiling in the myelodysplastic syndromes using cDNA microarray technology.

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal disorders of the haematopoietic stem cell and primarily involve cells of the myeloid lineage. Using cDNA microarrays comprising 6000 human genes, we studied the gene expression profiles in the neutrophils of 21 MDS patients, seven of which had the 5q- syndrome, and two acute myeloid leukaemia (AML) patients when compared with the neutrophils from pooled healthy controls. Data analysis showed a high level of heterogeneity of gene expression between MDS patients, most probably reflecting the underlying karyotypic and genetic heterogeneity. Nevertheless, several genes were commonly up or down-regulated in MDS. The most up-regulated genes included RAB20, ARG1, ZNF183 and ACPL. The RAB20 gene is a member of the Ras gene superfamily and ARG1 promotes cellular proliferation. The most down-regulated genes include COX2, CD18, FOS and IL7R. COX2 is anti-apoptotic and promotes cell survival. Many genes were identified that are differentially expressed in the different MDS subtypes and AML. A subset of genes was able to discriminate patients with the 5q- syndrome from patients with refractory anaemia and a normal karyotype. The microarray expression results for several genes were confirmed by real-time quantitative polymerase chain reaction. The MDS-specific expression changes identified are likely to be biologically important in the pathophysiology of this disorder.

Down-Regulation↗

PubMed2004

Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia.

The putative tumour suppressor gene gravin is down-regulated in several solid tumours and is implicated in tumorigenesis. We have evaluated the expression levels of the gravin gene in the CD34(+)/blast cells of a range of myeloid malignancies as compared with controls using real-time quantitative polymerase chain reaction (PCR). Gravin was markedly down-regulated in 41 of 41 patients with acute myeloid leukaemia (AML), nine of 10 patients with myelodysplastic syndromes (MDS) and 33 of 33 patients with chronic myeloid leukaemia (CML), of whom 24 were in blast crisis (BC). We have shown that gravin is consistently down-regulated in the CD34(+)/blast cells of myeloid malignancies and may play a role in the molecular pathogenesis of these disorders.

A Kinase Anchor Proteins↗

PubMed2003

Gene expression profiling in polycythemia vera using cDNA microarray technology.

Polycythemia vera (PV) is a myeloproliferative disorder characterized by an increased proliferation of all three myeloid lineages. The molecular pathogenesis of PV is unknown. Using cDNA microarrays comprising 6000 human genes, we studied the gene expression profile of granulocytes obtained from 11 PV patients compared with granulocytes obtained from healthy individuals. We found that 147 genes were up-regulated by >/==" BORDER="0">2.5 fold in the majority of PV patients. Eleven of these 147 genes were up-regulated in all PV patients studied and may represent a molecular signature for this disorder. An increase in the expression of several protease inhibitors with affinity for proteases that promote apoptosis in neutrophils (e.g., cystatin F, secretory leukocyte protease inhibitor), as well as the up-regulation of a number of antiapoptotic and survival factors was found (e.g., adrenomedullin, p38 mitogen-activated protein kinase). We speculate that the deregulation of these factors may inhibit normal apoptosis and promote cell survival in the granulocytes of patients with PV. These PV-specific expression changes are likely to be biologically important in the pathophysiology of this disorder.

Gene Expression Profiling↗

PubMed2003

Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS).

Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. But many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects should reflect a wider spectrum of mutations because they are not prone to negative selection in development. It has been difficult to identify such mutations so far, but microarray analysis provides a new opportunity to do so. Using this approach, we have shown that in individuals with myelodysplasia associated with alpha-thalassemia (ATMDS), somatic mutations of the gene encoding the chromatin remodeling factor ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene. These findings cast new light on this pleiotropic cofactor, which appears to be an essential component rather than a mere facilitator of globin gene expression.

Base Sequence↗