Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas

• Published in: Haematologica (Roma) 2007-04, Vol.92 (4), p.460-468
• Main Authors: Ripperger, Tim, von Neuhoff, Nils, Kamphues, Kathrin, Emura, Makito, Lehmann, Ulrich, Tauscher, Marcel, Schraders, Margit, Groenen, Patricia, Skawran, Britta, Rudolph, Cornelia, Callet-Bauchu, Evelyne, van Krieken, Johan H.J.M, Schlegelberger, Brigitte, Steinemann, Doris
• Format: Article
• Language: English
• Subjects: Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Biological and medical sciences; Cell Line, Tumor - drug effects; Cell Line, Tumor - metabolism; Chromosomes, Human, Pair 1 - genetics; Chromosomes, Human, Pair 11 - ultrastructure; Chromosomes, Human, Pair 14 - ultrastructure; Decitabine; Disease Progression; DNA Methylation; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing - drug effects; Genes, Tumor Suppressor; GTPase-Activating Proteins - biosynthesis; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - physiology; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Mantle-Cell - genetics; Lymphoma, Mantle-Cell - pathology; Medical sciences; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction - methods; Promoter Regions, Genetic - genetics; Transcription, Genetic - drug effects; Translocation, Genetic
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.10337

Institute of Cell and Molecular Pathology (TR, NVN, KK, ME, MT, BS, CR, BS, DS); Institute of Pathology, Hannover Medical School, Germany (UL); Department of Pathology, Radboud University Nijmegen, Medical Center, Nijmegen, the Netherlands (MS, PG, JHJMVK); Laboratoire d’Hematologie et de cytogénétique, Centre Hospitalier Lyon Sud, Lyon, France (EC-B). Correspondence: Doris Steinemann, Hannover Medical School, Institute of Cell and Molecular Pathology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail: steinemann.doris{at}mh-hannover.de Background and Objectives: Mantle cell lymphoma (MCL), a mature B-cell neoplasm, is genetically characterized by the translocation t(11;14)(q13;q32). However, secondary alterations are required for malignant transformation. The identification of inactivated tumor suppressor genes contributing to the development of MCL may lead to further elucidation of the biology of this disease and help to identify novel targets for therapy. Design and Methods: Whole genome microarray-based gene expression profiling on treated versus untreated MCL cell lines was used to identify genes induced by 5-aza-2'-deoxycytidine. The degree of promoter methylation and transcriptional silencing of selected genes was then proven in MCL cell lines and primary cases by methylation-specific polymerase chain reaction (PCR) techniques, real-time PCR and gene expression profiling. Results: After 5-aza-2'-deoxycytidine treatment, we identified more than 1000 upregulated genes, 16 of which were upregulated 3-fold. Most of them were not known to be silenced by methylation in MCL. A low expression of ING 1, RUNX 3 and BNIP 3 L was observed in three of the five the MCL cell lines. In addition, the expression of PARG1 , which is located in the frequently deleted region 1p22.1, was substantially reduced and displayed at least partial promoter methylation in all investigated MCL cell lines as well as in 31 primary MCL cases. Interpretation and Conclusions: In summary, we identified interesting novel candidate genes that probably contribute to the progression of MCL and suggest that PARG 1 is a strong candidate tumor suppressor gene in MCL. Key words: mantle cell lymphoma, epigenetic silencing, tumor suppressor gene, PTPL 1-associated RhoGAP1 ( PARG 1).