title: Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma.
abstract: Recently, we identified a novel chromosomal rearrangement in Hodgkin lymphoma (HL), t(4;8)(q27;q24), which targets homeobox gene ZHX2 at the recurrent breakpoint 8q24. This aberration deletes the far upstream region of ZHX2 and results in silenced transcription pinpointing loss of activatory elements. Here, we have looked for potential binding sites within this deleted region to analyze the transcriptional deregulation of this tumor suppressor gene in B-cell malignancies. SiRNA-mediated knockdown and reporter gene analyses identified two transcription factors, homeodomain protein MSX1 and bZIP protein XBP1, directly regulating ZHX2 expression. Furthermore, MSX1-cofactor histone H1C mediated repression of ZHX2 and showed enhanced expression levels in cell line L-1236. As demonstrated by fluorescence in situ hybridization and genomic array analysis, the gene loci of MSX1 at 4p16 and H1C at 6p22 were rearranged in several HL cell lines, correlating with their altered expression activity. The expression of XBP1 was reduced in 6/7 HL cell lines as compared to primary hematopoietic cells. Taken together, our results demonstrate multiple mechanisms decreasing expression of tumor suppressor gene ZHX2 in HL cell lines: loss of enhancing binding sites, reduced expression of activators MSX1 and XBP1, and overexpression of MSX1-corepressor H1C. Moreover, chromosomal deregulations of genes involved in this regulative network highlight their role in development and malignancy of B-cells.
authors.affiliation: Department of Human and Animal Cell Lines, DSMZ - German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, 38124 Braunschweig, Germany. sna@dsmz.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.forename: Björn
authors.initials: B
authors.lastname: Schneider
authors.forename: Corinna
authors.initials: C
authors.lastname: Meyer
authors.forename: Maren
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: Macleod
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D006689:Hodgkin Disease / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051957:MSX1 Transcription Factor / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C476826:ZHX2 protein, human