Short Telomeres Are Associated with Genetic Instability and the Occurrence of High Risk Genomic Aberrations in Chronic Lymphocytic Leukemia.

Telomere length has been associated with the mutation status of the immunoglobulin variable heavy chain (VH) gene and the clinical course in chronic lymphocytic leukemia (CLL). In an unicentric CLL cohort of 108 patients, we have analyzed the telomere length by quantitative real time PCR, genomic aberrations by FISH with a comprehensive set of DNA probes (11q, 12q, 13q, 14q, 17p), the VH mutation status by DNA sequencing, ZAP-70 expression (clone 2F3.2, Upstate, according to Crespo et al., NEJM 2003) and CD38 expression by flow cytometry, to further study the prognostic impact and associations among these factors. A relative telomere-single-copy-gene ratio (T/S) was calculated for each sample, where low and high T/S values correspond to short and long telomere lengths, respectively. The median T/S value was 0.33 (range 0.06–1.18). There was an inverse correlation between telomere length and the following parameters: 1. VH homology (r=−0.56, p<0.001), 2. CD38 expression (r=−0.44, p<0.001) and 3. ZAP-70 expression (r=−0.25, p=0.01). Cases with T/S values below the median of 0.33 (short telomeres) and cases with T/S values above the median (long telomeres) had similar incidences of genomic aberrations (76 vs. 67%), 13q- (54 vs. 52%) and +12q (9 vs. 9%). In contrast, 13q- as a single aberration was significantly more frequently observed in cases with long telomeres (43 vs. 17%, p=0.006), whereas 11q- (30 vs. 9%, p=0.014), 17p- (24 vs. 0%, p<0.001) and cases with two or more genomic aberrations (26 vs. 6%, p<0.001) were significantly more frequent in cases with short telomeres. Compared to cases with long telomeres the treatment free survival from diagnosis (TFS) and overall survival (OS) in the group with short telomeres were significantly shorter (TFS: 29 vs. 67 months, p=0.002; OS: last observed death at 100 months, survival probability 57% vs. last observed death at 141 months, survival probability 77%, p=0.02). In conclusion, telomere length was inversely correlated with the VH mutation status, CD38 expression and ZAP-70 expression. Short telomeres were associated with genomic instability indicated by a high number of aberrations and the occurrence of 11q- and 17p- in CLL. These observations have biological and prognostic implications in CLL.