title: t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2.
abstract: Hodgkin/Reed-Sternberg (HRS) cells represent the malignant fraction of infiltrated lymph nodes in Hodgkin lymphoma (HL). Although HRS cells display multiple chromosomal aberrations, few are recurrent and the targeted genes unknown. However, understanding the pathology of HL and developing rational therapies may well require identifying putative deregulated genes. Here, we analyzed the karyotype of the well-defined HL cell line L-1236 by spectral karyotyping and identified multiple abnormalities, therein, notably t(4;8)(q27;q24) which includes two breakpoint regions previously highlighted in HL. Target genes at 4q27 and 8q24 were shortlisted by high density genomic arrays and fluorescence in situ hybridization. Expression analysis of candidate target genes revealed conspicuous activation of phosphodiesterase PDE5A at 4q27 and inhibition of homeobox gene ZHX2 at 8q24. Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed against PDE5A and concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicating PDE5A as an oncogene. Expression profiling of L-1236 cells following siRNA-mediated knockdown of ZHX2 showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity of ZHX2. Downstream genes included STAT1 and several STAT1-target genes, indicating activation of STAT1-signaling by ZHX2 as analyzed by RQ-PCR and western blot. Taken together, we have identified a novel aberration with recurrent breakpoints in HL, t(4;8)(q27;q24), which activate PDE5A and repress ZHX2, deregulating apoptosis, differentiation, and STAT1-signaling in HL cells.
authors: Department of Human and Animal Cell Lines, DSMZ--German Collection of Microorganisms and Cell Cultures, Inhoffenstr. 7B, 38124 Braunschweig, Germany. sna@dsmz.de
authors: Stefan
authors: S
authors: Nagel
authors: Björn
authors: B
authors: Schneider
authors: Andreas
authors: A
authors: Rosenwald
authors: Corinna
authors: C
authors: Meyer
authors: Maren
authors: M
authors: Kaufmann
authors: Hans G
authors: HG
authors: Drexler
authors: Roderick A F
authors: RA
authors: MacLeod
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4; D002898:Chromosomes, Human, Pair 8; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques / Q000379:methods; D005801:Genes, Homeobox; D006689:Hodgkin Disease / Q000201:enzymology / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D007223:Infant; D059785:Karyotype; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D050794:STAT1 Transcription Factor / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D018398:Homeodomain Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014157:Transcription Factors; C476826:ZHX2 protein, human; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human