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Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells

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Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells Leukemia (2010) 24, 756–764 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells A Pellagatti1, M Cazzola2, A Giagounidis3, J Perry1, L Malcovati2, MG Della Porta2,MJa¨dersten4, S Killick5, A Verma6, CJ Norbury7, E Hellstro¨m-Lindberg4, JS Wainscoat1 and J Boultwood1 1LRF Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK; 2Department of Hematology Oncology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3Medizinische Klinik II, St Johannes Hospital, Duisburg, Germany; 4Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK; 6Albert Einstein College of Medicine, Bronx, NY, USA and 7Sir William Dunn School of Pathology, University of Oxford, Oxford, UK To gain insight into the molecular pathogenesis of the the World Health Organization.6,7 Patients with refractory myelodysplastic syndromes (MDS), we performed global gene anemia (RA) with or without ringed sideroblasts, according to expression profiling and pathway analysis on the hemato- poietic stem cells (HSC) of 183 MDS patients as compared with the the French–American–British classification, were subdivided HSC of 17 healthy controls. The most significantly deregulated based on the presence or absence of multilineage dysplasia. In pathways in MDS include interferon signaling, thrombopoietin addition, patients with RA with excess blasts (RAEB) were signaling and the Wnt pathways. Among the most signifi- subdivided into two categories, RAEB1 and RAEB2, based on the cantly deregulated gene pathways in early MDS are immuno- percentage of bone marrow blasts. Patients with 420% blasts deficiency, apoptosis and chemokine signaling, whereas advanced were classified as AML. MDS patients with o5% bone marrow MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene blasts and an isolated deletion of the long arm of chromosome expression profiles and deregulated gene pathways in patients 5 [del(5q)] were categorized as 5qÀ syndrome, and a new with del(5q), trisomy 8 or À7/del(7q). Patients with trisomy 8 category termed as MDS-unclassifiable was created incorporat- are characterized by deregulation of pathways involved in ing patients not fulfilling the other criteria. The main prognostic the immune response, patients with À7/del(7q) by pathways factors of MDS, for progression to AML and survival, include involved in cell survival, whereas patients with del(5q) show the number of cytopenias, percentage of marrow blasts and deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene cytogenetic abnormalities. These factors are combined in an pathways and ontology groups in the HSC of a large group of International Prognostic Scoring System that distinguishes four MDS patients. The deregulated pathways identified are likely to subgroups with distinct probabilities of progression to AML and be critical to the MDS HSC phenotype and give new insights survival.8,9 into the molecular pathogenesis of this disorder, thereby Early MDS (RA) are characterized by an increased apoptosis providing new targets for therapeutic intervention. in the bone marrow, which may in part underlie the ineffective Leukemia (2010) 24, 756–764; doi:10.1038/leu.2010.31; published online 11 March 2010 hematopoiesis and peripheral blood cytopenia found in these Keywords: gene expression pathways; myelodysplastic subgroups. In contrast, in advanced MDS (high-risk MDS), a syndromes; hematopoietic stem cells; gene expression profiling progressive increase in myeloblasts, coupled with a decrease in apoptosis, and increased genomic instability is observed.1,2 Karyotypic abnormalities are reported in about 50% of patients with primary MDS and 80% of patients with secondary MDS.10 The characteristic MDS abnormalities involve loss of Introduction genetic material, whereas balanced translocations are rare. The most common cytogenetic abnormalities in MDS include The myelodysplastic syndromes (MDS) are a heterogeneous the del(5q), trisomy 8 and À7/del(7q).10 Patients with the group of clonal hematopoietic stem cell (HSC) malignancies that 5qÀ syndrome, in which the del(5q) is the sole karyotypic are characterized by ineffective hematopoiesis resulting in abnormality, are characterized by a macrocytosis, anemia, peripheral cytopenias (thrombopenia, leucopenia and anemia) 1,2 normal or high platelet count and hypolobulated megakaryo- and typically a hypercellular bone marrow. The MDS are cytes in the bone marrow and a good prognosis.11–13 The pre-leukemic conditions showing frequent progression to acute presence of À7/del(7q) is associated with a frequent progression myeloid leukemia (AML). Approximately 40% of MDS patients 1,2 to AML, and chromosome 7 abnormalities are an indicator of a develop AML. MDS is one of the commonest myeloid 8 3,4 poor prognosis in the International Prognostic Scoring System. malignancies and is at least as common as AML. In comparison, MDS with trisomy 8 typically has an inter- The classification of MDS is based on morphologic anomalies mediate prognosis;8 peripheral blood cytopenias are often according to the French–American–British Cooperative Study 14 5 responsive to immunosuppressive treatment, and have a more Group. More recently, this classification has been modified by favorable prognosis. A number of gene abnormalities have been implicated in the development or progression of MDS, includ- Correspondence: Dr J Boultwood, Nuffield Department of Clinical ing, for example, mutations in the Ras, p53, RUNX1 and TET2 Laboratory Sciences, University of Oxford, LRF Molecular Haemato- genes.15,16 However, the molecular pathogenesis of MDS logy Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail: [email protected] remains incompletely understood. Received 29 October 2009; revised 15 December 2009; accepted 14 The disease course and prognosis are highly variable in MDS. January 2010; published online 11 March 2010 The majority of MDS patients will succumb to the disease over Deregulated pathways in myelodysplastic syndromes A Pellagatti et al 757 time, because of infection as a result of neutropenia and/or Microarray data analysis neutrophilic dysfunction or the development of AML.1,2 With Cell intensity calculation and scaling was performed using the exceptions of lenalidomide, which is effective in MDS with GeneChip Operating Software. Data analysis was performed the del(5q)17 and hypomethylating agents such as azacitidine, using GeneSpring 7.3.1 (Agilent Technologies). The GeneChip which is used to treat advanced MDS and may improve overall Operating software was used to perform quality control after survival by several months,18 there are few effective drug scaling the signal intensities of all arrays to a target of 100. The treatments for this disorder.19 MDS-associated leukemia does values obtained for scale factors, background levels, percentage not respond well to chemotherapy and patients have a poor of present calls, 30/50 GAPDH ratio and intensities of spike prognosis.1,2 Allogeneic stem cell transplantation remains the hybridization controls were within the acceptable range for all only option for curative treatment in MDS, yet is only applicable samples. Affymetrix CEL files were pre-processed using robust in 15–20% of all patients.20 The identification of new targets in multichip analysis.23 Data from 17 healthy controls were used to MDS for drug treatment is, therefore, of major importance. obtain patient/control expression ratios. Hierarchical clustering Recent studies have identified several core signaling pathways was performed with GeneSpring software using standard altered in the development of certain solid tumors, including correlation. Pathway analysis was performed using Ingenuity glioblastoma21 and pancreatic cancer,22 that greatly further our Pathway Analysis 7.5 software (Ingenuity Systems, Redwood understanding of the molecular pathogenesis of these malig- City, CA, USA) based on the Ingenuity Pathways Knowledge nancies and importantly may represent new targets for Base, which is the most comprehensive database of biological therapeutic intervention. findings. Gene ontology was performed using the Database for We have chosen to determine deregulated gene expression Annotation, Visualization and Integrated Discovery (DAVID). pathways and ontology (functional) groups in the CD34 þ cells The data discussed in this publication have been deposited of a large group of patients with MDS to advance our in NCBI’s Gene Expression Omnibus24 and are accessible understanding of these disorders. through GEO Series accession number GSE19429 (http:// www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc ¼ GSE19429). Materials and methods Real-time quantitative PCR The expression data for selected genes were validated in a Sample collection and cell separation subset of MDS patients (n ¼ 12) and controls (n ¼ 11) using real- A total of 183 patients with MDS and 17 healthy controls were time quantitative PCR. The b2-microglobulin gene was used included in the study. Classification of MDS patients was to normalize for differences in input cDNA. Pre-developed according to the French–American–British criteria,5 with RAEB TaqMan Assays were used (Assays-on-Demand,
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