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
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
Haematologica. 2007 Apr;92(4):460-8. doi: 10.3324/haematol.10337.
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.
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.
After 5-aza-2'-deoxycytidine treatment, we identified more than 1000 upregulated genes, 16 of which were upregulated > or =3-fold. Most of them were not known to be silenced by methylation in MCL. A low expression of ING1, RUNX3 and BNIP3L 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.
In summary, we identified interesting novel candidate genes that probably contribute to the progression of MCL and suggest that PARG1 is a strong candidate tumor suppressor gene in MCL.
套细胞淋巴瘤（MCL）是一种成熟B细胞肿瘤，其遗传学特征为t(11;14)(q13;q32)易位。然而，恶性转化还需要二次改变。鉴定对MCL发生发展起作用的失活肿瘤抑制基因，可能会进一步阐明该疾病的生物学特性，并有助于确定新的治疗靶点。
采用基于全基因组微阵列的基因表达谱分析，比较经5-氮杂-2'-脱氧胞苷处理与未处理的MCL细胞系，以鉴定由其诱导的基因。然后通过甲基化特异性聚合酶链反应（PCR）技术、实时PCR和基因表达谱分析，在MCL细胞系和原发性病例中证实所选基因的启动子甲基化程度和转录沉默情况。
经5-氮杂-2'-脱氧胞苷处理后，我们鉴定出1000多个上调基因，其中16个上调≥3倍。它们中的大多数在MCL中并不因甲基化而沉默。在5个MCL细胞系中的3个中观察到ING1、RUNX3和BNIP3L低表达。此外，位于常见缺失区域1p22.1的PARG1表达在所有研究的MCL细胞系以及31例原发性MCL病例中均显著降低，并显示至少部分启动子甲基化。
总之，我们鉴定出了可能与MCL进展相关的有趣新候选基因，并提示PARG1是MCL中一个强有力的候选肿瘤抑制基因。
