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 phosphodiesterasePDE5Aat 4q27 and inhibition of homeobox geneZHX2at 8q24. Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed againstPDE5Aand concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicatingPDE5Aas an oncogene. Expression profiling of L-1236 cells following siRNA-mediated knockdown ofZHX2showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity ofZHX2. Downstream genes includedSTAT1and several STAT1-target genes, indicating activation of STAT1-signaling byZHX2as 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 activatePDE5Aand repressZHX2, deregulating apoptosis, differentiation, and STAT1-signaling in HL cells. © 2011 Wiley Periodicals, Inc.