Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

Abstract

Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n 5 265) and in relation to other prognostic markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P < 0.0001). TL was an independent prognostic factor and subdivided patients with otherwise good-prognostic features (e.g., mutated IGHV genes, favorable cytogenetics) into subgroups with different outcome. Furthermore, in follow-up samples (n 5 119) taken 5-8 years after diagnosis, TL correlated well with TL at diagnosis and remained unaffected by treatment. Altogether, these novel data indicate that short TL already at diagnosis is associated with poor outcome in CLL and that TL can be measured at later stages of the disease. Am. J. Hematol. 88:647-651, 2013. V C 2013 Wiley Periodicals, Inc. IntroductionTelomeres are specialized structures at chromosome ends which serve to protect these ends from being recognized as DNA double-strand breaks. In addition, the repetitive telomere sequences serve as a buffer of non-gene coding DNA when the telomere ends shorten due to the "end replication problem." Telomere maintenance and integrity in hematopoietic cells is executed by telomerase adding new telomeric repeats to the ends in collaboration with telomere length regulators, i.e., the shelterins. The net result of these acting forces defines the actual cellular TL which can serve as a biomarker for telomere integrity and dysfunction. There is growing evidence that TL carries information of clinical importance for cancer patients. In general, malignant cells have shorter telomeres than their normal counterparts and there is an association between short telomeres and acquisition of genetic aberrations, risk of transformation and tumor progression [1][2][3]. Hence, TL as a potential clinical biomarker in cancer has gained considerable interest and its importance in hematological malignancies has been broadly investigated.Chronic lymphocytic leukemia (CLL), a heterogeneous disease with a variable outcome, can be subdivided into clinically relevant subgroups based on molecular, cytogenetic, and phenotypic features and a large set of potential prognostic biomarkers have been identified (reviewed in [4][5][6]). The future status of these biomarkers as a basis for clinical decision makings has not yet been fully defined, although the immunoglobulin heavy chain variable (IGHV) gene mutational status and in particular the presence of certain recurrent genomic aberrations (i.e., 11q2, 112, 13q2, 17p2) are commonly applied biomarkers [5][6][7]. Several studies have lately indicated TL as a potential prognostic marker in CLL, whereby short telomeres may predict poor clinical outcome [8][9][10][11][12][13][14][15]. Furthermore, a stro...

Telomere shortening associated with increased genomic complexity in chronic lymphocytic leukemia

“…Conversely, CLL cases with long TL were characterized by deletion 13q14, no cytogenetic alterations or only one abnormality. In agreement with our findings, a similar correlation between TL and the number of genomic aberrations was previously reported [12,17], supporting dysfunctional telomeres may be a key event driving genomic instability in tumors and correlate with the emergence of increased genomic complexity [25].…”

“…Our results in CLL support a role for telomere shortening at the origin of genomic instability [24] and reinforce previous reports showing the adverse prognostic value of chromosome alterations in this pathology [6,8,29]. In this line, Mansouri et al [17] found that an increased number of large copy number aberrations as detected by high resolution SNP-arrays correlated with decreasing TL in CLL patients. Rossi et al [16] showed that short telomeres are an independent predictor of Richter's syndrome transformation, process associated to increased genetic complexity.…”

“…Telomeric dysfunction has been proposed as an emerging prognostic factor in CLL as short telomere length (TL) was associated with unmutated status of the immunoglobulin heavy-chain variable region gene, high-risk genomic aberrations, and poor outcome [11][12][13][14][15]. Besides, an association between short TL and genetic complexity measured by fluorescence in situ hybridization (FISH) analysis and/or the large of copy number aberrations detected by high resolution SNParrays was described [12,16,17]. In this report, we have explored the relationship between TL and chromosome alterations, studied by FISH and conventional cytogenetics, in newly diagnosed CLL patients.…”

A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia

“…Mean inter-assay CV for relative telomere length was 4-8% 35 . Telomere/single copy gene values were calculated by 2 -ΔCt methodology.…”

ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres

“…The short telomeres were significantly associated with both reduced TTFT (medians 18 vs. 42 months for long telomeres; P=0.039) ( Figure 3A) and overall survival (OS) (medians 88 months vs. not reached for long telomeres; P=0.016) ( Figure 3B) in subset #2. Although a previous report showed relatively stable TL after treatment in CLL patients, 15 we cannot fully exclude an impact of therapy administration on survival analysis since a proportion of samples (24%) was collected after therapy. Regarding genetic defects, we also assessed their impact on OS.…”