Telomeres cap the ends of chromosomes, distinguishing the natural ends from dsDNA breaks, thus preventing aberrant recombination. Telomere function is conferred by the ‘shelterin’ protein complex, which associates with telomeric DNA repeats via the telomere-binding proteins, TRF1 and TRF2 [1]. Telomeric DNA is composed of the hexameric sequence TTAGGG tandemly repeated into arrays that display considerable length variation. Telomere length variation is apparent between individuals and is dependent upon age, disease status and lifestyle, as well as genetic factors that influence zygotic telomere length [2,3]. Semiconservative replication cannot fully replicate linear DNA molecules, and these end-replication losses result in a progressive shortening of telomeres with ongoing cell division [4,5]. This is counteracted by the enzyme telomerase, which is active in stem cell compartments, including hematopoietic stem cells, stimulated lymphocytes and 85% of human malignancies [6–8]. Whilst telomerase activity can maintain telomere length in the germline and malignant cells, in somatic stem cells and lymphocytes, telomerase activity is insufficient to completely ameliorate telomere erosion. As a consequence, there is telomere shortening in these cells as a function of cell division, either as a consequence of age or aberrant cell turnover in disease contexts [9]. Telomere length is an important determinant of telomere function and short telomeres ultimately lose their end-capping function, eliciting a p53-dependent DNA damage checkpoint response [10], which depending on the cell type, triggers either a permanent cell cycle arrest referred to as replicative senescence, or alternatively, apoptotic cell death. However, this checkpoint response does not result in the repair of the uncapped telomeres. This telomere-driven limitation to replicative lifespan is considered to confer a stringent tumor-suppressive mechanism in long-lived species, such as humans [11]. In malignancies, this mechanism is overcome by the upregulation of telomerase activity, or the activation of alternative telomere lengthening processes, that results in the stabilization of telomere length. In cell culture models, the absence of a functional DNA-damage checkpoint response enables cells to continue to divide beyond the point at which replicative senescence/apoptosis would be triggered [12]. This results in additional telomere erosion and ultimately, the complete loss of telomere function [13]. At this point telomeres are denuded of telomere repeats and are subjected to DNA repair mechanisms that result in the fusion of telomeres with other telomeres and nontelomeric dsDNA breaks [13,14]. This process leads, via cycles of anaphase bridging, breakage and further fusion, to large-scale genomic instability and ultimately cell death and the loss of the culture, a process referred to as ‘crisis’ [12]. Extrapolating from these observations, it has been considered that telomere erosion and dysfunction, in the absence of sufficient telomerase activity and in the context of compromised cell cycle checkpoints, could drive genomic instability in the early stages of tumor progression. As genomic instability increases, there will be selective pressure to upregulate telomerase activity and this in turn will restabilize the genome, locking in place the appropriate genomic rearrangements that may drive progression to malignancy. This model is consistent with evidence from telomerase knockout mice, where mice with short telomeres are tumor prone, and demonstrate a change in the spectrum of tumor types from mesenchymal tumors to carcinoma facilitated by the loss of p53 [15,16]. Tumors from these mice contain high frequencies of chromosomes lacking telomeric signals, anaphase bridges, nonreciprocal translocations and end-to-end fusions. Evidence for telomere dysfunction driving progression in human solid tumors is circumstantial, but convincing. Nonreciprocal translocations and aneuploidy are common in adult carcinomas [17–19]; nonreciprocal translocations, as well as localized amplifications and aneuploidy, are consistent with aberrations that can occur as a consequence of telomere dysfunction. The majority of malignancies in humans exhibit shorter telomeres compared with normal tissues [20–22], an observation that is consistent with increased cell division during the progression to malignancy. Higher frequency of anaphase bridging has been documented at the adenoma/hyperplasia–carcinoma transition in several solid tumor types [15,23,24], this transition point is also characterized by the upregulation of telomerase [7,25]. Several studies have now also provided significant association with variation at the 5p15.33 locus, which contains the TERT gene (encoding the catalytic subunit of telomerase), with several solid tumor types (reviewed in [26]). Thus, there is accumulating evidence for telomere-driven genomic instability during the progression to malignancy in solid tumors.
Could this telomere paradigm apply to leukemia?
Familial mutations in the components of the telomerase complex including hTERT, hTERC and DKC1 predispose to the bone marrow failure syndrome dyskeratosis congenita (DC). These mutations result in often extreme telomere shortening in this condition [27]. DC patients are predisposed to cancer [28,29]; this includes a 196-fold increase in the frequency of acute myeloid leukemia (AML) [29] and this may be related to the high level of chromosome instability observed in this condition [30,31]. Other bone marrow failure syndromes, such as Fanconi anemia, Shwachman–Diamond syndrome, Diamond–Blackfan anemia and aplastic anemia, also display a failure of telomere length maintenance [32–35] and higher rates of myeloid leukemia [36–38]. Following these observations, it has become apparent that constitutive telomere mutations are implicated in up to 8% of sporadic AML cases [39]. Mutations in hTERT and hTERC have, in addition to mutations in RUNX1 and CEBPA [40,41], been implicated in familial cases of myelodysplastic syndromes (MDS) with AML [42]; disease anticipation is also observed that is consistent with progressive telomere shortening in the germline between generations [27,42]. Thus, deficiencies in telomere maintenance are clearly implicated in leukemia.
Consistent with the observations in solid tumors, telomerase expression and activity is readily detected in hematological malignancies [43–51], albeit in some at comparatively low levels, and it is also clear that leukemic malignancies exhibit significant telomere shortening. In chronic myeloid leukemia (CML) patients, Philadelphia chromosome-containing stem cells exhibit shorter telomeres, which are inversely correlated with a high-risk Hasford score [52,53]. This telomere erosion has been attributed to increased proliferation of the CML clone, as opposed to telomere erosion prior to the formation of the Philadelphia chromosome. Telomere erosion in MDS/AML has been documented and correlated with increasing genomic complexity [54–56] and risk of progression [57], and is observed in therapy-related MDS after autologous hematopoietic stem cell transplant [58]. Numerous reports have documented telomere erosion in chronic lymphocytic leukemia (CLL), and this is correlated with the presence of specific markers of progression including key genomic rearrangements, such as loss of heterozygosity (LOH) at 17p [48,59–64]. Telomere shortening has also been documented in mantle cell lymphoma [65], and comparisons between B-cell neoplasms indicate that mantle cell lymphoma cells exhibit shorter telomeres than CLL, followed by multiple myeloma and marginal zone lymphoma with follicular and Burkitt’s lymphomas exhibiting longer telomeres [64].
Large-scale genomic rearrangements are also common in hematological malignancies and these include nonreciprocal translocations that are consistent with telomere dysfunction [16,66]. Reciprocal translocations leading to specific molecular rearrangements are a key driver of tumorigenesis in the majority of myeloid leukemias, with different subclassifications exhibiting distinct rearrangements [67]. The underlying mechanisms that drive the reoccurrence of specific translocations in the context of the entire human genome have not been established. However, the characterization of translocations has revealed microhomologies and deletions at the breakpoints [68,69], a similar profile to that observed following the fusion of short dysfunctional telomeres [14,50,70]; this profile is characteristic of error-prone nonhomologous end joining. These reciprocal translocations are also accompanied by other specific genomic rearrangements, as well as numerous sporadic rearrangements [101,102]; these include the types of rearrangements consistent with telomere dysfunction. These observations imply the possibility of a telomere-driven chromosomal instability phenotype that facilitates these rearrangements during the development of myeloid leukemias.
The observations showing telomere shortening in hematological malignancies, together with the correlations that have been made between telomere erosion and the occurrence of genomic rearrangements, are consistent with the view that telomere dysfunction can drive genomic instability and progression in these conditions. However, the simple measurements of mean telomere length, for example, using quantitative FISH or terminal restriction fragment analysis, can only provide evidence of global telomere shortening. These techniques are not able to provide direct evidence that telomere shortening is sufficient to trigger telomere dysfunction and fusion principally because they are unable to detect the shortest telomeres. Thus, it still remains possible that telomere erosion is a biomarker of cell turnover [71], and genomic instability is driven by other processes [72–74]. Recently, this issue has been addressed by the development of high-resolution technologies to determine telomere length and fusion. Of particular importance is the unique ability of these technologies to detect the presence of extreme telomere shortening and to detect and characterize the DNA sequence of telomere fusion events [14,70,75,76]. Using these technologies to examine telomere dynamics in vitro, it is apparent that telomeres lose their end-capping function, and are subject to fusion at a mean telomere length of 35 bp (just 5.8 TTAGGG repeats); the longest telomeres that has been documented to be subjected to fusion in these studies is 43 repeats (258 bp) [14,70]. Telomeres of these lengths are not represented in other telomere length assays. These technologies are now being used to examine the full extent of telomere dynamics in hematological malignancies. In CLL, extreme telomere shortening has been observed [50]. Indeed, telomere lengths in some CLL B cells were indistinguishable from those observed in cells undergoing ‘crisis’ in culture, where telomere dysfunction clearly drives large-scale genomic rearrangements [13,14]. Importantly, direct evidence of telomere dysfunction in the form of telomere fusion events was observed only in CLL B cells exhibiting the shortest telomere length distributions; again, the frequencies of telomere fusion were similar to those observed in ‘crisis’ cells in vitro. Furthermore, CLL B cells showing direct evidence of telomere dysfunction (fusion or telomeric LOH) also exhibited large-scale genomic mutation, with multiple rearrangements involving the chromosome ends. Importantly, telomere shortening and fusion were also observed in early-stage patients, indicating that telomere dysfunction can occur prior to clinical disease progression. This observation raises the possibility that telomere length analysis, using high-resolution tools, might be useful in predicting the prognosis of patients with early-stage disease. Taken together, these data provide strong evidence that CLL B cells suffer a period of telomere-driven genomic instability. The extreme telomere shortening observed in CLL indicates that some loss of cell cycle checkpoint control must have occurred to facilitate telomere erosion to similar lengths observed in cells that would otherwise induce a p53-dependent DNA damage response. Thus, one scenario could be that mutations in genes within the p53 DNA damage pathway compromise the ability of CLL B cells to respond to telomere dysfunction. Continued cell division facilitates further telomere erosion and loss of the end-capping function. The resulting telomere fusion events then initiate a cascade of genomic instability that can drive LOH and complete loss of checkpoint control, which in turn promotes clonal evolution [50]. It remains to be seen whether the paradigm that we have described in CLL is applicable to other human leukemias. However, the low-resolution telomere data that already exist, coupled with the common occurrence of mutations or deletions in key DNA checkpoint regulators, provide circumstantial evidence for a key role for telomere erosion in the pathology of a number of other hematological malignancies. The application of high-resolution telomere analysis to other types of leukemias will allow us to directly assess the role of telomere dysfunction in the pathology of these tumors.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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