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Gene Expression Profiling Distinguishes JAK2 V617F-Negative

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Gene Expression Profiling Distinguishes JAK2 V617F-Negative Leukemia (2008) 22, 1368–1376 & 2008 Macmillan Publishers Limited All rights reserved 0887-6924/08 $30.00 www.nature.com/leu ORIGINAL ARTICLE Gene expression profiling distinguishes JAK2V617F-negative from JAK2V617F-positive patients in essential thrombocythemia E Puigdecanet1,2,3,4, B Espinet1,3,5, JJ Lozano6,7, L Sumoy6, B Bellosillo1, L Arenillas2,3,5,AA´ lvarez-Larra´n8, F Sole´1,3,5, S Serrano1,2,3, C Besses8 and L Florensa2,3,5 1Laboratori de Citogene`tica i Biologia Molecular, Servei de Patologia. Hospital del Mar, IMAS, Barcelona, Spain; 2Laboratori de Citologia Hematolo`gica, Servei de Patologia, Hospital del Mar, IMAS, Barcelona, Spain; 3GRETNHE, IMIM-Hospital del Mar, Barcelona, Spain; 4Departament de Biologia Cellular, Fisiologia i Immunologia. Facultat de Biocie`ncies. Universitat Auto`noma de Barcelona, Bellaterra, Spain; 5Escola de Citologia Hematolo`gica Soledad Woessner-IMAS, Barcelona, Spain; 6Laboratori de Microarrays, Programa de Bioinforma`tica i Geno`mica, Centre de Regulacio´ Geno`mica-UPF, Barcelona, Spain; 7Plataforma de Bioinforma´tica, CIBERehd, Hospital Clinic, Barcelona, Spain and 8Servei d’Hematologia Clı´nica, Hospital del Mar, IMAS, Barcelona, Spain To explore the gene expression signature in essential throm- 50–60% of ET and PMF patients).2–6 Although the description of bocythemia (ET) patients in relation to JAK2V617F mutational the JAK2V617F mutation has provided important insight into the status, expression profiling in circulating granulocytes was performed. Twenty ET were studied by microarray analysis and pathogenesis of PV, ET and PMF, the molecular abnormalities the results were confirmed by real-time quantitative RT-PCR associated to JAK2V617F-negative BCR-ABL-negative MPD in 40 ET patients, not receiving cytoreductive treatment. A remain unknown. Regarding ET, JAK2V617F-positive patients heterogeneous molecular signature characterized by two main present clinical features resembling the PV phenotype, in gene expression patterns was found: one with an upregulation contrast to JAK2V617F-negative ET patients, and according to of inflammatory genes related to neutrophil activation and this observation, two molecular distinct subtypes of ET have thrombosis, and the other with significantly lower expression of 7 these genes. Supervised clustering analysis showed 30 genes been proposed. The constitutive kinase activity of V617F differentially expressed between JAK2V617F-negative and mutation causes cytokine-independent activation of the JAK- JAK2V617F-positive ET patients. Among the JAK2V617F-nega- STAT, PI3K-AKT and Ras-MAPK pathways. This multiple path- tive, a set of 14 genes (CISH, C13orf18, CCL3, PIM1, MAFF, way activation results in the independence or hypersensitivity of SOCS3, ID2, GADD45B, KLF5, TNF, LAMB3, HRH4, TAGAP and haematopoietic progenitors to numerous cytokines, a hallmark TRIB1) showed an abnormal expression pattern. In this group of MPD.2–5 Recently, mutations involving exon 12 of the JAK2 of patients, CISH, SOCS2, SOCS3 and PIM1 genes, all involved 8,9 in JAK-STAT signalling pathway, presented a lower expression. gene in PV and MPLW515L mutation in approximately 10% A two-gene predictor model was built comprising FOSB and of JAK2V617F-negative PMF and in a smaller proportion of ET 10 CISH genes, which were the best discriminators of JAK2V617F have been reported. However, in more than 40% of ET status. In conclusion, JAK2V617F-negative ET patients present patients a molecular marker is still lacking. a characteristic gene expression profile, different from Global gene expression analysis has been used as a powerful JAK2V617F-positive patients. Other pathways, besides JAK- tool to provide insight into the molecular aetiology of STAT, might be implicated in the pathophysiology of haematologic malignancies. Granulocytes with altered gene JAK2V617F-negative ET patients. 11–13 Leukemia (2008) 22, 1368–1376; doi:10.1038/leu.2008.112; expression have been detected in PV and new markers have 14 published online 15 May 2008 been defined in relation to JAK2V617F. Recently, distinct gene Keywords: essential thrombocythemia; JAK2V617F; gene expression subclasses in ET in relation to JAK2V617F status have expression profiling; real-time quantitative RT-PCR been described by using cDNA microarrays.15 Our aim was to characterize the gene expression profile of peripheral blood granulocytes in ET using whole genome oligonucleotide microarray technology and real-time quantita- Introduction tive RT-PCR. The objective was to extend the set of markers for ET and analyse the relation between gene expression data, BCR-ABL-negative myeloproliferative disorders (MPDs) includ- JAK2V617F status and clinical manifestations of the disease. ing polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are characterized by a clonal expansion of a multipotent haematopoietic progenitor cell. ET is Patients and methods a heterogeneous entity characterized by increased bone marrow megakaryocytes, persistent thrombocytosis and an increased risk Patients of thrombohaemorrhagic complications.1 Recently, the exis- A total of 40 cases (28 women/12 men) with a median age of tence of the JAK2V617F mutation has been reported in a high 54 years (ranging from 31 to 85 years), diagnosed with ET proportion of MPD BCR-ABL-negative patients (90% of PV, according to the WHO criteria (2001), who had never received cytoreductive treatment were studied. At the time of diagnosis Correspondence: Dr L Florensa, Laboratori de Citologia Hematolo`gica, four patients had presented thrombotic events and three patients Servei de Patologia-GRETNHE, Hospital del Mar, Pg. Marı´tim, had shown haemorrhages. Among the 40 patients, 32 presented 25-29, Barcelona 08003, Spain. E-mail: [email protected] at least one of the following clonality markers: JAK2V617F, Received 4 July 2007; revised 2 April 2008; accepted 4 April 2008; positivity for HUMARA assay and myeloid endogenous growth. published online 15 May 2008 JAK2V617F was detected in 52.5% (21/40) patients, always in Gene expression profiling in essential thrombocythemia E Puigdecanet et al 1369 heterozygosity, with a percentage of mutant alleles ranging Each microarray was hybridized with 750 ng of each from 7.8 to 40.7% (mean of 28.3%). Among the 17 out of 28 amplified cRNA labelled with Cy5 or Cy3 at a specific activity informative women, seven showed clonality by the HUMARA between 7 and 15 pmol/mg. Duplicate hybridizations were assay. Out of 40 patients, 26 showed endogenous myeloid performed for each comparison with dye swapping to control growth (eBFU-E and/or eCFU-MK). Out of 19 JAK2V617F- for possible differences in the incorporation rate of the Cy5 negative patients, 11 presented HUMARA clonality and/or and Cy3 fluorochromes. Microarray expression profiles were myeloid endogenous growth. Therefore, only eight patients did obtained using Whole Human Genome oligonucleotide micro- not present any clonal marker. We analysed the association arrays (G4112A, Agilent), comprising 41 000 60-nt oligonucleo- between presence or absence of JAK2V617F and clinico- tide probes, most represented as single spots, using the protocol biological data from all patients (Table 1). Ten healthy recommended by Agilent with SSC-based washes. individuals (5 women/5 men) with age ranging from 25 to 58 years and with a normal blood cell count were used as assay Scanning and analysis. Fluorescent images were obtained validation controls. The study was approved by the local ethics using an Agilent G2565BA scanner. Fluorescence intensity data were committee and written informed consent was obtained from all extracted and quantified using Genepix 6.0 (Molecular Dynamics). patients, according to the Declaration of Helsinki. Only spots with signal intensities twice above the local background, not saturated and not flagged as absent by GenePix, were considered reliable and used for subsequent RNA extraction analysis. Normalized log2ratios were scaled between arrays to Venous blood (20 ml) was collected in ethylendiaminetetraace- make all data comparable. Statistically significant differences in tic acid (EDTA) and immediately processed. Granulocytes were gene expression were determined by computing a Bayesian 16 isolated as previously described and total cellular RNA from statistic using all log2ratios from replicate hybridizations. 6 each sample was isolated from 10 Â 10 granulocytes using a Target genes were considered as differentially expressed guanidinium thiocyanate-based method (Ultraspec; Biotecx when their empirical Bayes statistic B was higher than 15 Laboratories, Houston, TX, USA) following the protocol (B_rank498%). All quantitative and statistical analyses were supplied by the manufacturer. performed using MMARGE tool, a web implementation of the RNA quality was assessed by nanoelectrophoresis using the Limma package in the R environment.17,18 Nano lab-on-a-chip assay for total eukaryotic RNA (Bioanalyzer, Supervised classification of ET samples into categories Agilent Technologies, Palo Alto, CA, USA). Only samples with according to clinical and biological parameters based on gene RNA integrity number 47 were subsequently used in micro- expression profiles was performed using standard two-tailed array experiments. Student’s test using the t-test function from R (http://www.cran. r-project.org) and was used to determine statistical significance of differential gene expression. Gene Ontology terms for Microarray analysis annotated genes and common pathways were analysed using RNA
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