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Gene Expression Profiling in the Leukemic Stem Cell Leukemia (2011) 25, 1825–1833 & 2011 Macmillan Publishers Limited All rights reserved 0887-6924/11 www.nature.com/leu ORIGINAL ARTICLE Gene expression profiling in the leukemic stem cell-enriched CD34 þ fraction identifies target genes that predict prognosis in normal karyotype AML HJM de Jonge1,7, CM Woolthuis2,7,AZVos2, A Mulder3, E van den Berg4, PM Kluin5, K van der Weide2, ESJM de Bont6, G Huls2, E Vellenga2,8 and JJ Schuringa2,8 1Department of Experimental Hematology and Department of Pediatrics, Division of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 2Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 3Department of Clinical Chemistry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 4Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 5Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands and 6Department of Pediatrics, Division of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands In order to identify acute myeloid leukemia (AML) CD34 þ - subgroup (60%), treatment outcome varies considerably. Within specific gene expression profiles, mononuclear cells from AML þ À the intermediate risk group, subgroups are recognized based on patients (n ¼ 46) were sorted into CD34 and CD34 subfrac- mutations in the nucleophosmin 1 (NPM1) (leading to cytoplas- tions, and genome-wide expression analysis was performed þ using Illumina BeadChip Arrays. AML CD34 þ and CD34À gene mic dislocalization of NPM1 (NPM1c )) and fms-related tyrosine expression was compared with a large group of normal CD34 þ kinase 3 (FLT3) genes or based on biallelic mutations in the 3–5 bone marrow (BM) cells (n ¼ 31). Unsupervised hierarchical CEBP a gene. Identification of novel molecular markers might clustering analysis showed that CD34 þ AML samples belonged therefore be helpful for further risk stratification. In recent years, a to a distinct cluster compared with normal BM and that in 61% þ number of gene expression profiling (GEP) studies has been of the cases the AML CD34 transcriptome did not cluster performed in order to improve the identification of known together with the paired CD34À transcriptome. The top 50 of þ cytogenetic subgroups and to recognize new clusters of AML AML CD34 -specific genes was selected by comparing the 6–11 AML CD34 þ transcriptome with the AML CD34À and CD34 þ patients with distinct gene-expression signatures. Most of normal BM transcriptomes. Interestingly, for three of these these AML GEP studies have been performed using the total genes, that is, ankyrin repeat domain 28 (ANKRD28), guanine AML–mononuclear cell (MNC) fraction.6–9 As cell lineage and nucleotide binding protein, alpha 15 (GNA15) and UDP-glucose differentiation stages affect gene expression-based clustering,6,7,10 pyrophosphorylase 2 (UGP2), a high transcript level was the differentially expressed genes associated with the differentia- associated with a significant poorer overall survival (OS) in two independent cohorts (n ¼ 163 and n ¼ 218) of normal tion stage might obscure more basic gene expression information karyotype AML. Importantly, the prognostic value of the related to tumor initiation and maintenance. Consequently, continuous transcript levels of ANKRD28 (OS hazard ratio profiling of a more homogenous leukemic cell population, (HR): 1.32, P ¼ 0.008), GNA15 (OS HR: 1.22, P ¼ 0.033) and UGP2 instead of the total MNC fraction, might enhance the feasibility (OS HR: 1.86, P ¼ 0.009) was shown to be independent from the þ of using GEP to identify novel prognostic markers. well-known risk factors FLT3-ITD, NPM1c and CEBPA muta- AML is thought to be initiated and maintained by relatively tion status. Leukemia (2011) 25, 1825–1833; doi:10.1038/leu.2011.172; small numbers of leukemia-initiating cells that have an published online 15 July 2011 enhanced self-renewal capacity and can engraft in immuno- Keywords: Acute myeloid leukemia; gene expression profiling; deficient mice.12,13 In the vast majority of leukemias, leukemia- leukemic stem cells; prognostic factors; CD34 þ cells; transcriptome initiating cells have been found to reside in the CD34 þ analysis compartment.12–17 Studies aimed at further enrichment of leukemia-initiating cells revealed substantial heterogeneity in cell surface marker expression,18–23 and it has been observed that leukemia-initiating cells can reside both in the CD34 þ / Introduction CD38À and in the CD34 þ /CD38 þ fractions.24 In our current study, AML–MNC fractions were sorted in CD34 þ and CD34À Acute myeloid leukemia (AML) is clinically, cytogenetically and subfractions and gene expression was compared with a large molecularly a heterogeneous disease, which makes it challenging group of normal CD34 þ bone marrow (BM) cells. Thus, to classify it properly. Currently, patients diagnosed with AML are we were able to identify AML CD34 þ -specific gene expres- stratified into separate risk groups based on morphological, sion profiles, which included a number of genes that could cytogenetic and molecular abnormalities.1,2 However, especially significantly predict prognosis in normal-karyotype AML in the intermediate risk group that represents the largest AML independent of already established prognostic factors. Correspondence: Dr JJ Schuringa or E Vellenga, Department of Experimental Hematology, University Medical Center Groningen, Hanzeplein 1, Groningen, Groningen 9713 GZ, The Netherlands. Materials and methods E-mail: [email protected] or [email protected] 7Shared first authorship. 8Shared senior authorship. Patient material Received 15 December 2010; revised 12 May 2011; accepted 8 June GEP was performed on blast cells of 46 patients with AML 2011; published online 15 July 2011 from a single center (University Medical Center Groningen). Gene expression profiling in AML CD34 þ cells HJM de Jonge et al 1826 The diagnosis of AML was based on cytological examination, Table 1 Patient characteristics (n ¼ 46) immunophenotyping and cytogenetic analysis of blood and BM. AML blasts were collected from peripheral blood (PB) or BM Age (years) (n ¼ 7) after achieving informed consent. For 3 out of 46 Median 55 patients, cells from relapsing disease were used and one AML Range 20–80 was preceded by a myelodysplastic syndrome. The study was White blood cell count ( Â 109/L) approved by the Medical Ethical Committee of the UMCG. Median 45.8 MNCs were isolated by density gradient centrifugation using Range 2.2–229.3 lymphoprep (PAA, Co¨lbe, Germany) and cryopreserved. After thawing, CD34 þ and CD34À AML cells were selected by Blast percentage MoFLo sorting (Dako Cytomation, Carpinteria, CA, USA) using a Median 64 CD34 PE-labeled antibody (Clone 8G12, BD Biosciences, Range 12–98 San Jose, CA, USA). Cytogenetic risk group distinction (favor- French–American–British classification (no. (%)) able, intermediate, and unfavorable) according to current M0 3 (7%) 25–27 HOVON/SAKK protocols is provided in Table 1. Potential M1 9 (20%) donors for allogeneic BM transplantation and patients who M2 12 (26%) underwent elective total hip replacement served as normal M4 3 (7%) controls (n ¼ 31) after providing informed consent. From the M5 17 (37%) M6 1 (2%) normal BM aspirates the MNC fraction was isolated and CD34- M7 1 (2%) enriched fractions were obtained using anti-CD34 magnetic beads (Clone QBEND/10, Miltenyi Biotec, Auburn, CA, USA). Cytogenetic characteristicsFno. (%)a We realize that differences in procedures that were used to t(8;21) 4 (9%) isolate CD34 þ cells from NBM and AML samples may have inv(16) 2 (4%) resulted in some changes at the transcriptome level. Nevertheless, t(v;11)(v;q23) 4 (9%) þ del(5q) 4 (9%) we currently do not have indications that different CD34 Normal karyotype 24 (52%) populations were obtained via these methods as different Complex cytogenetic abn. (X3) 10 (22%) antibodies were used, or that these potential differences in Other 5 (11%) transcriptomes were main determinants in our clustering analyses. Risk group according to HOVON/SAKKFno. (%)b Good 3 (7%) Intermediate 29 (63%) Analysis of mutations in NPM1 and FLT3 Poor 13 (28%) Detection of NPM1 mutations was performed by immunohisto- Unknown 1 (2%) chemical staining on BM biopsies that were fixed in 10% neutral phosphate buffered formalin (3.6% formaldehyde) for at least FLT3/NPM1Fno. (%) 12 h, and decalcified in a solution containing 10% (v/v) acetic FLT3 wt/NPM1 wt 26 (57%) acid and 10% formalin (v/v; 3.6% formaldehyde) for 1 or 2 days. FLT3-ITD/NPM1 wt 10 (22%) FLT3 wt/NPMc+ 1 (2%) Detection of NPM1 localization was performed on paraffin FLT3-ITD/NPMc+ 9 (20%) embedded 3 mm tissue sections by immunohistochemical staining Abbreviations: FLT3, fms-related tyrosine kinase 3; ITD, internal using a Benchmark XT (Ventana Medical Systems S.A., Tucson, + AZ, USA). The antigens were retrieved with EDTA buffer (pH 8.5) tandem duplication; NPM1, nucleophosmin 1; NPMc , cytoplasmic dislocalization of NPM1; wt, wild type. and endogenous peroxidase was blocked with H2O2. Slides were aPatients may be counted more than once owing to the coexistence of incubated with 1:50 diluted supernatant of the biotinylated more than one cytogenetic abnormality. anti-NPM1 antibody (kindly provided by Prof. Falini, Perugia, bRisk group distinction was made based on current HOVON/SAKK Italy). Antigens were visualized using the ultraview universal protocols with favorable risk: t(15;17), t(8;21) and WBC p20 Â 109/l at DAB detection kit (Ventana). Exclusive nuclear versus a diagnosis, or inv(16)/t(16;16) and no unfavorable cytogenetic abn.; combined nuclear and cytoplasmic localization of the protein unfavorable risk: inv(3) or t(3;3), t(6;9), t(v;11)(v;q23) other than t(9;11), À5 or del(5q), À7, abn(17p), complex karyotype (three or more was scored by an experienced hematopathologist.
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