title: Aberrantly Expressed OTX Homeobox Genes Deregulate B-Cell Differentiation in Hodgkin Lymphoma.
abstract: In Hodgkin lymphoma (HL) we recently reported that deregulated homeobox gene MSX1 mediates repression of the B-cell specific transcription factor ZHX2. In this study we investigated regulation of MSX1 in this B-cell malignancy. Accordingly, we analyzed expression and function of OTX homeobox genes which activate MSX1 transcription during embryonal development in the neural plate border region. Our data demonstrate that OTX1 and OTX2 are aberrantly expressed in both HL patients and cell lines. Moreover, both OTX loci are targeted by genomic gains in overexpressing cell lines. Comparative expression profiling and subsequent pathway modulations in HL cell lines indicated that aberrantly enhanced FGF2-signalling activates the expression of OTX2. Downstream analyses of OTX2 demonstrated transcriptional activation of genes encoding transcription factors MSX1, FOXC1 and ZHX1. Interestingly, examination of the physiological expression profile of ZHX1 in normal hematopoietic cells revealed elevated levels in T-cells and reduced expression in B-cells, indicating a discriminatory role in lymphopoiesis. Furthermore, two OTX-negative HL cell lines overexpressed ZHX1 in correlation with genomic amplification of its locus at chromosomal band 8q24, supporting the oncogenic potential of this gene in HL. Taken together, our data demonstrate that deregulated homeobox genes MSX1 and OTX2 respectively impact transcriptional inhibition of (B-cell specific) ZHX2 and activation of (T-cell specific) ZHX1. Thus, we show how reactivation of a specific embryonal gene regulatory network promotes disturbed B-cell differentiation in HL.
authors.affiliation: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.affiliation: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrentraut
authors.affiliation: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Kaufmann
authors.affiliation: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.affiliation: Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: MacLeod
mesh_terms: D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006410:Hematopoiesis / Q000235:genetics; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051857:Otx Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016539:Reed-Sternberg Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C497659:OTX2 protein, human; D051857:Otx Transcription Factors