Relevance of telomere/telomerase system impairment in early stage chronic lymphocytic leukemia.
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.
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.
Mirjam
M
Hoxha
Sonia
S
Fabris
Luca
L
Agnelli
Valentina
V
Bollati
Giovanna
G
Cutrona
Serena
S
Matis
Anna Grazia
AG
Recchia
Massimo
M
Gentile
Agostino
A
Cortelezzi
Fortunato
F
Morabito
Pier Alberto
PA
Bertazzi
Manlio
M
Ferrarini
Antonino
A
Neri
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D019175:DNA Methylation; D020869:Gene Expression Profiling; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D012189:Retrospective Studies; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics*; D059506:Telomere Shortening
C509186:TERT protein, human; D019098:Telomerase