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REVIEW the Role of Homeobox Genes in Normal Hematopoiesis And Leukemia (1999) 13, 1675–1690 1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu REVIEW The role of Homeobox genes in normal hematopoiesis and hematological malignancies JW van Oostveen1, JJ Bijl2, FM Raaphorst2, JJM Walboomers2 and CJLM Meijer2 Departments of 1Hematology and 2Pathology, University Hospital, Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands In the last decade it has become clear that homeobox contain- Table 1 Grouping of gene families, coding for transcription fac- ing genes (HOX genes) not only play a significant role in reg- tors, according to their DNA binding motif,244 and their reported func- ulating body formation, but in addition, they are contributing tions to organization and regulation of hematopoiesis. Modern mol- ecular technologies showed that deregulated expression or DNA binding- Gene (family) Function disruption of Hox genes can lead to altered characteristics of domain blood cells or disturbance of blood cell development. In this paper we review the role of HOX proteins in hematopoiesis and leukemogenesis and speculate about their possible target Helix-turn-helix HOX genes embryonic genes and involvement in lymphomagenesis. development, Keywords: transcription factors; homeobox genes; embryogen- organogenesis, esis; hematopoiesis; lymphoma; adhesion hematopoiesis Zinc finger GATA genes/E2A/Pax5 hematopoiesis, endodermal differentiation245 Transcription factors Zinc finger LIM Rbtn2/Lmo2 Embryonic red blood family cells265 Runt AML1(CBFA2) Fetal liver Transcription factors are sequence-specific DNA-binding pro- 266 teins with a variety of functions: some are thought to help fold hematopoiesis Basic helix- SCL gene (tal-1)/c-myc hematopoietic the DNA molecule into distinct domains; others assist in the loop-helix proteins/E2A commitment and initiation of DNA replication, and many control gene tran- differentiation194,246,247 scription. Binding affinity to DNA sequences, the concen- Basic leucine c-fos/c-jun Proliferation248 tration of transcription factors and the presence of cofactors zipper are important determinants in gene activation. Transcription Winged helix forkhead/HNF-3 family embryogenesis, liver factors can be classified according to the three-dimensional organogenesis, tumorigenesis249 structure of their DNA-binding domains. More than 80% of ETS domain ets family Hematopoiesis31,250 all transcription factors are characterized by zinc finger, helix- Rel homology Rel/NF-kappa B family regulation of immune turn-helix, helix-loop-helix, leucine zipper and winged helix domain and inflammatory motifs (Table 1). Moreover, the complexity of transcriptional processes, communication regulation is increased by formation of functional hetero- or 251 homodimers of transcription factors (for instance c-fos and c- between cells 1 HMG-box HMG family (Tcf-1/Lef-1) B and T cell jun ), or by participation in large protein complexes (for development252 instance c-myc). Transcription of a particular gene is an event regulated by a complex network of transcription factors. The HNF-3, hepatocyte nuclear factor; HMG, high mobility group; HOX, total set of transcription factors present in a cell – induced by homeobox; the Table is modified from Clevers HC, Grosschedl R. extracellular signals – provides a specific genetic imprint that Transcriptional control of lymphoid development: lessons from results in a distinct response. Transcription factors have a gene targeting. Immunol Today 1996; 17: 336–343. regulatory role in proliferation and in all kinds of differen- tiation processes, like embryogenesis, organogenesis, and also hematopoiesis (Table 1).2–9 ensure its own survival by proliferation before differentiating into all lineages of blood cells. This balance of proliferation and differentiation is highly dynamic, and pluripotent stem Hematopoiesis cells and progenitor cells are produced in relation to physio- logical stresses of the organism (such as bleeding, or Specialized blood cells of all lineages originate from the pluri- infection). The intriguing question arises how this process of potent stem cell by hematopoiesis. Blood cells have a limited blood cell development is controlled, and which genes are life-span, and new cells are generated continuously through- involved in this complex process. out life. The ancestral pluripotent stem cell must therefore Hematopoiesis during embryogenesis Correspondence: JW van Oostveen, Department of Hematology, Uni- The anatomical site of hematopoiesis changes during early life versity Hospital Vrije Universiteit (VU), De Boelelaan 1117 Amster- 10 11 dam, PO Box 7057, NL-1007 MB Amsterdam, The Netherlands; Fax: phases (reviewed by Zon and Auerbach ). During 31 20 4442601 embryogenesis, early hematopoiesis occurs in the yolk sac, Received 30 December 1998; accepted 12 July 1999 starting in humans at day 15 and continuing for 6 weeks. Review JW van Oostveen et al 1676 Hematopoietic stem cells – derived from the ventral meso- early hematopoietic progenitor cells into the lymphoid lin- derm – and vascular progenitors migrate to the yolk sac to eage.43,44 Several other genes specifically involved in the lym- form blood cell islands.12 These islands consist of an endoder- phopoiesis have been found, such as Pax5/BSAP, E2A, Oct-2, mal layer (supporting growth), a central core of hematopoietic PU.1, Ets-1 and Tcf-1.45–53 Of these transcription factors both stem cells, and an endothelial layer that surrounds the blood Pax5 and Oct-2 genes belong to the HOX class II genes, which islands.13 Although progenitors of most blood cells are contain a homeobox in addition to another characteristic present, these stem cells predominantly differentiate into sequence (see below). erythroid cells and occasionally into monocytes and megakar- yocytes.14–16 They are primarily important for embryonic hem- atopoiesis17 and die during further development of the Development of the lymphoid lineage embryo. In the embryo itself, an additional population of hem- atopoietic stem cells is present in the dorsal mesentery (also The stem cell first differentiates into a lymphoid and a myeloid called the aorta gonad mesonephros region, or AGM). This progenitor cell. All lymphocytes are derived from a common population initiates definitive hematopoiesis (including that of lymphoid progenitor cell. Differentiation is accompanied by the lymphoid lineage), first in fetal liver and spleen, and sub- changes in morphology and immunophenotype, eg loss of sequently in bone marrow (BM).17 BM remains the primary stem cell marker CD34 during differentiation and induction hematopoietic organ in adult life. Developmentally controlled of lineage-specific markers such as CD19 and CD22. Lympho- changes in location of blood cell development requires coor- cytes are responsible for the body’s response to foreign anti- dinate regulatory decisions in cell fate and reorganization of gen. As the number of potential antigens is enormous, this cells. requires a large pool of lymphocytes, each displaying speci- ficity for a single antigen. Antigen responses are divided into the humoral immune response, mediated by B cells, and the Transcription factors in hematopoiesis cellular immune response, mediated by T cells. Stimulated by specific cytokines like IL–7 and Flt3 ligand, Hematopoiesis includes many decisions in lineage commit- B cells initially develop in the BM. Their maturation is ment that depend on coordinate expression of lineage-specific accompanied by rearrangement of immunoglobulin (Ig) genes genes. This development program is governed by transcription encoding their membrane-associated antigen receptor. This factors. Blood cell development is particularly complex produces a large population of B cells each expressing their because it occurs at different body sites, partly determined by unique Ig molecules. Immature B cells with a self-reactive developmental stage. Fetal hematopoiesis occurs in the liver, receptor are negatively selected before they leave the BM. whereas in adults it is initiated in BM. Lymphoid cells reach After migration and homing to lymph nodes, follicular B cells their final maturation stage in peripheral lymphoid organs, that recognize the appropriate antigen on follicular dendritic such as lymphnodes, spleen and extranodal lymphoid tissues. cells continue to mature in the germinal center reaction.54 The microenvironment of these specific body sites has a pro- During this process cells with an antigen-specific Ig receptor found influence on the differentiation program.18,19 Therefore, are selected to survive,55 and will further differentiate into genes that can specify positional information, such as homeo- plasma cells and memory B cells. Cells without antigen speci- box (HOX) genes, might be strongly related with the control ficity, or expressing a self-specific antigen receptor, undergo of hematopoiesis.20 programmed cell death (apoptosis). Expression studies have revealed a number of transcription T cell development occurs primarily in a separate organ, factor genes that are active in specific cell lineages and differen- the thymus. This gland is formed from the third pharyngeal tiation stages during hematopoiesis. Their function was clarified pouch and consists of well-defined cortical and medullar in vitro by transfection studies, and in vivo by knock-out and zones. Immature prothymocytes enter the thymus, attracted by transgenic mice experiments. Disruption of transcription factor chemotactic factors. Here, they interact with stromal
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