Prognostic Significance of Telomere Length in Chronic Lymphocytic Leukemia Patients in Early Stage Disease,

Abstract 3890

Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease with a variable outcome. The identification of factors that could predict the clinical course of early-stage CLL represents a crucial objective. Although previous studies indicated that telomere length may be a useful independent prognostic factor in the risk stratification of CLL, limited information has been reported in asymptomatic early stage patients (Binet stage A). We investigate the association of telomere length with the major biological and cytogenetic markers known to predict clinical outcome in CLL. The global DNA methylation levels of Alu and LINE sequences, was also investigated. Correlation with disease progression, measured as the time elapsed from diagnosis to first treatment, was evaluated. We measured relative telomere length (RTL) by real-time PCR in a panel of highly purified (>90%) peripheral mononuclear CD19+ cells from 7 healthy donors and 77 untreated CLLs. All the cases were characterized by FISH for the most frequent chromosomal aberrations (Fabris et al. GCC, 2008). Molecular markers including mutation status of the heavy chain variable regions of immunoglobulin genes (IGVH), the expression of the 70-kd zeta-chain T-cell receptor-associated protein kinase (ZAP-70) and CD38 cell surface antigen protocols were previously reported (Cutrona et al., Haematologica, 2008). A quantitative bisulfite-PCR Pyrosequencing method was used to evaluate methylation of Alu and LINE-1. We found a significantly lower RTL values in CLLs (median RTL=0.4 IQR 0.3–0.6) as compared with controls (median RTL=1.0 IQR 0.9–1.3) (P <0.001). A progressive and significant RTL decrease in low (13q- and normal karyotype), intermediate (+12) and high (11q- and 17p-) cytogenetic risk categories (P for trend =0.008) was observed. Patients with IGVH mutated genes had longer telomeres than patients with unmutated genes (P <0.001). No significant association between telomere length and either CD38 or ZAP-70 expression was found. Telomere shortening was significantly correlated with hypomethylation of Alu (P =0.048) and LINE-1 (P =0.001), indicating a contribution to chromosome instability. Finally, follow-up analysis showed a significantly higher risk of starting treatment for patients with shorter telomeres (P =0.0037). Our results extended previous evidence that telomere length could be used as marker for the identification of CLLs with a different prognostic risk.