Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia

Abstract

Telomere length is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). In a B-CLL cohort of 152 patients, we analyzed telomere length, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression to study the prognostic impact and associations among these factors. An inverse correlation existed between telomere length and IGHV homology (P < .001), CD38 (P < .001), and ZAP-70 expression (P ‫؍‬ .01). Patients with telomere lengths below median (ie, "short telomeres") and above median (ie, "long telomeres") had similar incidences of genomic aberrations (74% vs 68%), 13q؊ (57% vs 49%), and ؉12q (5% vs 12%). In contrast, 13q؊ as a single aberration was more frequent in patients with long telomeres (51% vs 21%; P ‫؍‬ .006), whereas 11q؊ (27% vs 9%; P ‫؍‬ .014), 17p؊ (17% vs 0%; P < .001), and 2 or more genomic aberrations (39% vs 8%; P < .001) were more frequent in patients with short telomeres.Compared with patients with long telomeres, treatment-free survival (TFS) and overall survival (OS) was significantly shorter (P < .001 and P ‫؍‬ .015, respectively) in the group with short telomeres, and telomere length was an independent prognostic indicator for TFS. IntroductionB-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in adults in the Western world, is characterized by a monoclonal expansion of mature B lymphocytes expressing CD19, CD5, and CD23 on the cell surface. 1 B-CLL is a clinically heterogeneous disease with survival times ranging from months to normal lifespan. 2 As a consequence of the variable clinical course, it has become very crucial to identify reliable prognostic factors useful in planning therapeutic strategies and predicting the outcome. A number of biological features of B-CLL have been described, and several of them can be used to discern different groups of patients with significant differences in clinical course and outcome. The immunoglobulin heavy chain variable (IGHV) gene mutation status analysis reveals 2 subgroups of B-CLL, [3][4][5] with a more favorable clinical course for patients with mutated IGHV genes. [6][7][8][9] The surface marker CD38 has been proposed as a surrogate marker for IGHV gene mutation status in B-CLL, 3 but the association between these markers was shown to be rather weak. 7-11 Furthermore, CD38 has been shown to be an independent prognostic marker, although no consensus has been reached concerning cut-off levels. 7,8,[11][12][13] Expression of the protein tyrosine kinase ZAP-70 is strongly associated with IGHV gene mutation status and can be used as an independent prognostic factor. 14-16 Although discordant results have been reported lately, certain IGHV gene usage (eg, and presence of high-risk genomic aberrations (eg, 11qϪ and 17pϪ) can explain these findings at least in part. 17,18 In mature B-cell neoplasms, telomere length correlates with histopathogenesis according to the germinal center. 19 This feature includes B-CLL showing a...

Extreme telomere erosion in ATM-mutated and 11q-deleted CLL patients is independent of disease stage

“…This is apparent from deuterated water incorporation experiments 1 as well as telomere erosion. [2][3][4] We have recently shown that the telomere erosion observed in CLL patients is extensive and can result in the loss of telomere function resulting in telomeretelomere fusion events, some of which were clonal; 5 this work also revealed telomeric loss of heterozygosity as well as largescale genomic rearrangements that were concomitant with telomere dysfunction. Telomere dysfunction may therefore account for clonal evolution and the occurrence of large-scale genomic rearrangements, including the loss of 17p and 11q, that confer a poor prognosis and are associated with short telomeres.…”

“…Telomere dysfunction may therefore account for clonal evolution and the occurrence of large-scale genomic rearrangements, including the loss of 17p and 11q, that confer a poor prognosis and are associated with short telomeres. 3 Short telomeres and telomeric DNA damage are also associated with the development of resistance to DNA damage-induced apoptosis. 6 The telomere dynamics described in CLL are indistinguishable from those observed experimentally in fibroblast cells undergoing a telomere driven 'crisis' in culture following the abrogation of the p53 pathway.…”

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia

“…25,26 Subsequent reports outlined the existence of patients in which discordance exists between TL and IGHV-MS and suggested a superior predictive value of TL. 28,29 Finally, Roos et al 47 were able to link TL with poor cytogenetics in a series of 152 patients, including samples collected both at diagnosis and after treatment. Notably, the independent effect of TL on OS was not demonstrated in any of the previously published reports.…”

“…This same validation procedure used for TL is commonly used to corroborate clinically and/or biologically based prognostic indicators and has been used also in the CLL field in a recent analysis comparing the relative value of CD38, ZAP70 and VHMS. [47][48][49] The identification and validation of a robust cutoff point is a prerequisite for widespread application of any biomarker. Previous studies in CLL used the median or the mean value of TL, ranging from 4300 to 6000 bp among series, to perform survival comparisons.…”

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

“…In the last years telomere length (TL) has been intensively studied in relation to risk and survival of various cancer types, including hematological ones. 5,26,37,38 In particular in a very recent study performed within the European prospective investigation on cancer (EPIC), Hosnijeh et al 39 have shown that longer telomeres are associated with increased risk of MM. In most epidemiological studies TL is measured in DNA from peripheral blood and used as a proxy for TL in other tissues.…”