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Profiling Cell Development by Gene Expression Characterization Of Characterization of Early Stages of Human B Cell Development by Gene Expression Profiling This information is current as Marit E. Hystad, June H. Myklebust, Trond H. Bø, Einar A. of September 28, 2021. Sivertsen, Edith Rian, Lise Forfang, Else Munthe, Andreas Rosenwald, Michael Chiorazzi, Inge Jonassen, Louis M. Staudt and Erlend B. Smeland J Immunol 2007; 179:3662-3671; ; doi: 10.4049/jimmunol.179.6.3662 Downloaded from http://www.jimmunol.org/content/179/6/3662 Supplementary http://www.jimmunol.org/content/suppl/2008/03/12/179.6.3662.DC1 Material http://www.jimmunol.org/ References This article cites 59 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/179/6/3662.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Characterization of Early Stages of Human B Cell Development by Gene Expression Profiling1 Marit E. Hystad,* June H. Myklebust,*ʈ Trond H. Bø,† Einar A. Sivertsen,* Edith Rian,* Lise Forfang,* Else Munthe,‡ Andreas Rosenwald,§ Michael Chiorazzi,¶ Inge Jonassen,†# Louis M. Staudt,¶ and Erlend B. Smeland2*ʈ We have characterized several stages of normal human B cell development in adult bone marrow by gene expression profiling of hemopoietic stem cells, early B (E-B), pro-B, pre-B, and immature B cells, using RNA amplification and Lymphochip cDNA microarrays Hierarchical clustering of 758 differentially expressed genes clearly separated the five populations. We used gene sets to .(6 ؍ n) investigate the functional assignment of the differentially expressed genes. Genes involved in VDJ recombination as well as B lineage- associated transcription factors (TCF3 (E2A), EBF, BCL11A, and PAX5) were turned on in E-B cells, before acquisition of CD19. Several transcription factors with unknown roles in B lymphoid cells demonstrated interesting expression patterns, including ZCCHC7 and ZHX2. Downloaded from Compared with hemopoietic stem cells and pro-B cells, E-B cells had increased expression of 18 genes, and these included IGJ, IL1RAP, BCL2, and CD62L. In addition, E-B cells expressed T/NK lineage and myeloid-associated genes including CD2, NOTCH1, CD99, PECAM1, TNFSF13B, and MPO. Expression of key genes was confirmed at the protein level by FACS analysis. Several of these Ags were heterogeneously expressed, providing a basis for further subdivision of E-B cells. Altogether, these results provide new information regarding expression of genes in early stages of human B cell development. The Journal of Immunology, 2007, 179: 3662–3671. http://www.jimmunol.org/ arly human B cell development occurs in the bone mar- cific recombination enzymes RAG1, RAG2, and TdT (6). The ex- row (BM)3 as hemopoietic stem cells (HSC) develop via pression of pre-BCR, composed of IgH chains and surrogate L E various B lineage-restricted precursors into immature B chains (VpreB and ␭14.1), is a hallmark for the pre-B cell popu- (IM-B) cells, which then leave the BM and enter the periphery. lation. Signaling through pre-BCR promotes L chain (VJL) rear- The different stages can be identified by the expression of CD Ags rangement and allelic exclusion at the Ig H chain locus. Once VJL and the rearrangement status of Ig H and L chains, and the current rearrangements are successful, L chains are expressed and combine consensus is that B lineage-committed cells pass through a with H chains as well as Ig␣/Ig␤ to form a functional BCR expressed ϩ ϩ Ϫ CD34 CD10 CD19 common lymphoid progenitors (CLP) early on IM-B cells. by guest on September 28, 2021 B (E-B) stage before they mature via CD34ϩCD19ϩCD10ϩ Early B cell development is controlled by a hierarchical regu- pro-B, CD34ϪCD19ϩ large pre-B I and II, and CD34ϪCD19ϩ latory network of transcription factors including PU.1, E2A, EBF, small pre-B II into CD34ϪCD19ϩsIgMϩ IM-B cells (1, 2). Galy et and Pax5 (7). E2A and EBF are required for the initiation of E-B al. (3) were the first to identify human CLP by demonstrating that cell development by regulating the expression of B lineage-spe- CD34highLinϪCD10ϩ cells had B, T, NK, and dendritic cell po- cific genes, including PAX5, which is essential for B cell com- tential. Later studies have indicated that this population is biased mitment maintenance (8, 9). Furthermore, development of lym- toward B lineage development and termed the population E-B cells phoid cells is supported by cytokines and interactions with stromal (4, 5). Rearrangements of the VDJ H chain locus are characteristic cells, as demonstrated by in vitro studies of human B cell devel- of pro-B cells and require the expression of the lymphocyte-spe- opment (10). Genome-wide gene expression profiling has been performed in murine precursor B cells (11, 12). Recently, van Zelm et al. (13) *Department of Immunology, Institute for Cancer Research, Rikshospitalet-Radium- hospitalet Medical Centre, Oslo, Norway; †Department of Informatics, University of investigated the Ig gene rearrangement steps in correlation to the Bergen, Bergen, Norway; ‡Institute of Pathology, Faculty Division Rikshospitalet, transcription factor expression of developing B cells from the BM University of Oslo, Oslo, Norway; §Institute of Pathology, University of Wurzburg, Wurzburg, Germany; ¶Metabolism Branch, National Cancer Institute, Bethesda, MD of healthy children. However, whereas the later stages of human B 20892; and ʈCentre for Biomedicine, University of Oslo, Oslo, Norway; and #Com- lineage development are well-characterized, the transitions from putational Biology Unit, University of Bergen, Bergen, Norway HSC into B lineage-committed cells have been explored in less Received for publication May 21, 2007. Accepted for publication June 20, 2007. detail. The aim of this study was to characterize the earliest steps The costs of publication of this article were defrayed in part by the payment of page of human B cell development in adult BM by gene expression charges. This article must therefore be hereby marked advertisement in accordance profiling. Total RNA was extracted from HSC, E-B, pro-B, pre-B, with 18 U.S.C. Section 1734 solely to indicate this fact. and IM-B cell populations from human BM, amplified, and hy- 1 This work was supported by the Norwegian Cancer Society, the Norwegian Re- search Council, and the Functional Genomics (FUGE) Program of the Norwegian bridized to Lymphochip cDNA microarrays. Altogether, this study Research Council. provides new insight into the molecular processes that take place 2 Address correspondence and reprint requests to Dr. Erlend B. Smeland, Department of in early human B cell differentiation. Immunology, Institute of Cancer Research, Rikshospitalet-Radiumhospitalet Medical Centre, 0310 Oslo, Norway. E-mail address: [email protected] 3 Abbreviations used in this paper: BM, bone marrow; HSC, hemopoietic stem cell; Materials and Methods E-B, early B; IM-B, immature B; CLP, common lymphoid progenitors; MPO, my- Cell separation and FACS analysis eloperoxidase; FDR, false discovery rate; GO, Gene Ontology; GC, germinal center; MEF, myocyte enhancer factor; MLP, multilineage progenitor cells; ALL, acute lym- BM aspirates from healthy adult donors were obtained after informed con- phoblastic leukemia. sent and approval by the Ethics Committee of the Norwegian Radium www.jimmunol.org The Journal of Immunology 3663 Table I. List of Abs and fixation/permeabilization methods used in FACS analysis and in cell-sorting experiments Used at Concentration Ab Company (Prod. No.) (␮g/ml) IgM FITC DakoCytomation (F0203) 1/40 dilution CD10 PE-Cy7 BD Biosciences (341102) 0.50 CD10 allophycocyanin BD Biosciences (332777) 0.60 CD34 allophycocyanin BD Biosciences (345818) 2.50 CD34 PE BD Biosciences (345802) 2.50 CD38 FITC Beckman Coulter (A07778) 0.30 CD38 PC5 Beckman Coulter (A07780) 0.80 CD38 PE DakoCytomation (R7144) 2.50 CD19 PC5 Beckman Coulter(A07771) 1.25 CXCR4 PE BD Biosciences (555974) 1/10 dilution CD62L BD Biosciences (341012) 1.00 CD2 FITC DakoCytomation (F0767) 2.50 CD127 PE Immunotech (PN IM1980) 1/5 dilution J chaina (rabbit) Gift from P. O. Brandtzaeg 1.25 Preimunized rabbit seruma Gift from P. O. Brandtzaeg 1.25 TdT FITCb DakoCytomation (F7139) Bcl-2 PEb BD Biosciences (340576) MPO PEc DakoCytomation (R7209) Downloaded from IgG1 FITC DakoCytomation (X0927) IgG2a FITC DakoCytomation (X0933) IgG1 PE DakoCytomation (X0928) IgG2b PE DakoCytomation (X0951) IgG2a PE BD Biosciences (349053) IgG1 allophycocyanin BD Biosciences (345818) IgG1 PECy7 BD Biosciences (348808) http://www.jimmunol.org/ IgG1 PC5 Beckman Coulter (A07798) a The cells were fixed in 4% paraformaldehyde for 10 minutes at room temperature, washed once in PBS, and then perme- abilized in 0.1% Triton-X 100 for 30 min at room temperature, washed once in PBS, and incubated with 50% methanol for 10 min at room temperature, washed twice in PBS, and then stained with the intracellular Ab. The anti-J chain Ab was a gift from P. O. Brandtzaeg, Oslo, Norway. b The cells were fixed and permeabilized by incubating with 100% methanol for 10 min at room temperature, washed once in PBS, and then stained with anti-J-chain Ab.
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