Hoxha Mirjam, Fabris Sonia, Agnelli Luca, Bollati Valentina, Cutrona Giovanna, Matis Serena, Recchia Anna Grazia, Gentile Massimo, Cortelezzi Agostino, Morabito Fortunato, Bertazzi Pier Alberto, Ferrarini Manlio, Neri Antonino
Department of Clinical Sciences and Community Health, Center of Molecular and Genetic Epidemiology, University of Milan, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Genes Chromosomes Cancer. 2014 Jul;53(7):612-21. doi: 10.1002/gcc.22171. Epub 2014 Apr 4.
Several studies have proposed telomere length and telomerase activity as prognostic factors in chronic lymphocytic leukemia (CLL), whereas information addressing the role of telomere-associated genes is limited. We measured relative telomere length (RTL) and TERT expression levels in purified peripheral CD19(+) B-cells from seven healthy donors and 77 untreated CLLs in early stage disease (Binet A). Data were correlated with the major biological and cytogenetic markers, global DNA methylation (Alu and LINE-1), and clinical outcome. The expression profiles of telomere-associated genes were also investigated. RTL was decreased in CLLs as compared with controls (P < 0.001); within CLL, a progressive and significant RTL shortening was observed in patients from 13q- through +12, 11q-, and 17p- alterations; short telomeres were significantly associated with unmutated IGHV configuration and global DNA hypomethylation. Decreased RTL was associated with a shorter time to first treatment. A significant upregulation of POT1, TRF1, RAP1, MRE11A, RAD50, and RPA1 transcript levels was observed in CLLs compared with controls. Our study suggests that impairment of telomere/telomerase system represents an early event in CLL pathogenesis. Moreover, the correlation between telomere shortening and global DNA hypomethylation supports the involvement of DNA hypomethylation to increase chromosome instability. © 2014 Wiley Periodicals, Inc.
多项研究提出端粒长度和端粒酶活性可作为慢性淋巴细胞白血病（CLL）的预后因素，而关于端粒相关基因作用的信息有限。我们检测了来自7名健康供者和77例疾病早期（Binet A期）未经治疗的CLL患者纯化外周血CD19(+) B细胞中的相对端粒长度（RTL）和TERT表达水平。数据与主要生物学和细胞遗传学标志物、整体DNA甲基化（Alu和LINE-1）以及临床结局相关。我们还研究了端粒相关基因的表达谱。与对照组相比，CLL患者的RTL降低（P < 0.001）；在CLL患者中，从13q-到 +12、11q-和17p-改变的患者观察到RTL呈进行性且显著缩短；短端粒与未突变的IGHV构型和整体DNA低甲基化显著相关。RTL降低与首次治疗时间缩短相关。与对照组相比，CLL患者中POT1、TRF1、RAP1、MRE11A、RAD50和RPA1转录水平显著上调。我们的研究表明，端粒/端粒酶系统受损是CLL发病机制中的早期事件。此外，端粒缩短与整体DNA低甲基化之间的相关性支持DNA低甲基化参与增加染色体不稳定性。© 2014威利期刊公司
