Search

The prognosis for patients with Hodgkin lymphoma (HL) has improved in recent decades. On the other hand, not all patients can be cured with the currently established therapy regimes and this therapy is associated with several adverse late effects. Therefore it is necessary to develop new therapy strategies. After treatment of L-540 HL cells with 5′-azacytidine (5AC), we observed increased expression of the preferentially expressed antigen in melanoma (PRAME). In addition, we detected an increased resistance of 5AC-treated cells against cytotoxic drugs. We analyzed the influence of PRAME on cell survival of HL cells by knocking down PRAME in the chemotherapy resistant cell line L-428, a cell line that express PRAME at a high level. After knock-down of PRAME using vector based RNA interference we observed increased sensitivity for cisplatin, etoposide and retinoic acid. DNA microarray analysis of HL cells after PRAME knock-down indicated regulation of several genes including down-regulation of known anti-apoptotic factors. Increased retinoic acid signaling in these cells was revealed by increased expression of the retinoic acid metabolizing cytochrome P450 (CYP26B1), a transcriptional target of retinoic acid signaling. Our data suggest that PRAME inhibits retinoic acid signaling in HL cells and that the knock-down of PRAME might be an interesting option for the development of new therapy strategies for patients with chemo-resistant HL. [ABSTRACT FROM AUTHOR]

Objective: The prognosis of patients with Hodgkin''s lymphoma (HL) has been significantly improved as a result of combination treatment including chemotherapy. However, some patients are refractory to chemotherapy. Therefore, identification of new targets might be useful for development of alternative treatment strategies. In addition, identification of markers associated with chemoresistance can be used to identify patients with increased risk of relapse. Materials and Methods: By using high-density DNA microarrays, we analyzed the gene-expression profile of HL-cell lines in comparison to a set of normal tissues. Furthermore, we tested the sensitivity of HL cells for cytotoxic drugs (cisplatin, etoposide, melphalan) and compared the gene-expression profile of chemotherapy-resistant and -sensitive cell lines. Differentially expressed genes were validated by polymerase chain reaction and flow cytometry. Results: In addition to genes with high expression in all cell lines, we observed differences between the gene-expression profile of chemotherapy-resistant and -sensitive cells. Genes upregulated in resistant cells include cytokine receptors (IL5RA, IL13RA1), markers expressed on antigen-presenting cells (CD40, CD80), as well as genes with known association to chemoresistance, e.g., myristoylated alanine–rich protein kinase C substrate. In addition, the tumor antigen PRAME (preferentially expressed antigen in melanoma) was expressed in resistant cell lines only. Conclusion: Genes with high expression in HL cells might be potential targets for development of future therapeutic interventions. Expression of tumor antigens together with costimulatory molecules in chemotherapy-resistant HL cells might become targets for cytotoxic T–cell responses against HL cells. [Copyright &y& Elsevier]