Telomere length and telomerase levels delineate subgroups of B-cell chronic lymphocytic leukemia with different biological characteristics and clinical outcomes

Abstract

Background: B-cell chronic lymphocytic leukemia is a clinically heterogeneous disease; some patients rapidly progress and die within a few years of diagnosis, whereas others have a long life expectancy with minimal or no treatment. Telomere length and telomerase levels have been proposed as prognostic factors; however, very few cases have been characterized for both parameters and no study has analyzed the prognostic value of the telomere/telomerase profile.

Design and methods: One hundred and seventy-three cases of chronic lymphocytic leukemia were characterized for telomere lengths and telomerase levels by real-time polymerase chain reaction. Data were correlated with established prognostic markers, IGVH mutational status and chromosomal aberrations, and clinical outcome.

Results: Telomere lengths were inversely correlated with telomerase levels (r(s) = -0.213; P = 0.012), and most of the cases of chronic lymphocytic leukemia with high levels (above median) of telomerase had short (below median) telomeres (P = 0.0001). Telomerase levels were higher and telomeres were shorter in unmutated IGVH cases than in mutated IGVH ones (P<0.0001). Chronic lymphocytic leukemias with 11q, 17p deletion or 12 trisomy had significantly higher levels of telomerase and shorter telomeres than those with no chromosomal aberration or the sole 13q deletion (P < 0.001). Telomere length/telomerase level profiles identified subgroups of patients with different clinical outcomes (P < 0.0001), even within the subsets of chronic lymphocytic leukemia defined by IGVH mutational status or chromosomal aberrations. Short telomere/high telomerase profile was independently associated with more rapid disease progression.

Conclusions: Comprehensive analyses of telomeres, telomerase, chromosomal aberrations, and IGVH mutational status delineate groups of chronic lymphocytic leukemias with distinct biological characteristics and clinical outcomes. The telomere/telomerase profile may be particularly useful in refining the prognosis of chronic lymphocytic leukemia patients with mutated IGVH and no high-risk chromosomal aberrations.

Figure 1.

Levels of hTERT transcripts and telomere lengths in B-CLL samples. (A) hTERT levels (hTERTcopies/10⁶ GAPDH copies) in B-CLL samples. The line indicates the median value. (B) Relationship between hTERT levels and relative units of telomerase activity. (C) Telomere length (T/S ratio) in B-CLL samples. The line indicates the median value. (D) Inverse relationship between hTERT levels and telomere length.

Figure 2.

Levels of hTERT transcripts (hTERTcopies/10⁶ GAPDH copies) and telomere lengths (T/S ratio) in B-CLL samples, according to (A, B) IGVH mutational status, (C, D) CD38 expression and (E, F) ZAP-70 expression.

Figure 3.

Levels of hTERT transcripts (hTERTcopies/10⁶ GAPDH copies) and telomere lengths (T/S ratio) in B-CLL samples, according to (A, B) the chromosomal categories (normal, 11q- 17p-, 13q- as the sole abnormality, and +12), and (C, D) lymphocyte doubling time (LDT). The P value refers to the overall trend of all groups in each graph. Pairwise comparisons between hTERT, T/S and chromosomal categories or LDT are shown in Online Supplementary Tables S1 and S2.

Figure 4.

hTERT level, telomere length, and hTERT level/telomere length profile according to (A, B) IGVH mutational status (mutated or unmutated), and (C, D) chromosomal categories (normal, 11q-or 17p-, 13q- as the sole chromosomal abnormality, and +12). hTERT low: ≤median value; hTERT high: >median value; T/S short ≤median value; T/S long>median value.

Figure 5.

Curves of treatment-free survival [time from diagnosis to first treatment (TTFT)], according to (A) hTERT level, (B) telomere length, and (C) hTERT level/telomere length profile. hTERT low: ≤median value; hTERT high: >median value; T/S short: ≤median value; T/S long: >median value. The median (95% CI) of TTFT and hazard ratios (95%) are provided in Online Supplementary Table S3.

Figure 6.

Curves of treatment-free survival [time from diagnosis to first treatment (TTFT)], according to (A) IGVH mutational status, (B) IGVH mutational status and hTERT level/telomere length profile, (C) high-risk (11q- or 17p-, +12) and low-risk (normal, 13q-) chromosomal categories, (D) chromosomal categories and hTERT level/telomere length profile, (E) IGVH mutational status, chromosomal categories, and hTERT level/telomere length profile. hTERT low: ≤median value; hTERT high: >median value; T/S short ≤median value; T/S long: >median value. The median (95% CI) of TTFT and hazard ratios are provided in Online Supplementary Table S3 (panel A, C), S4 (panel B) and S5 (panel E).