Telomeric impact of conventional chemotherapy

Abstract

The increased level of chromosome instability in cancer cells, leading to aneuploidy and gross chromosomal rearrangements, is not only a driving force for oncogenesis but also can be the Achille’s heel of the disease since many chemotherapies (CT) kill cells by inducing a non-tolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplasic drugs. These results raise the interesting possibility that CT with genotoxic drugs preferentially target telomeres. In agreement with this view, accelerated shortening of telomere length has been described in blood lineage cells following high-dose CT (stem cell transplantation) or non-myeloablative CT. However, almost nothing is known on the consequences of this shortening in terms of telomere stability, senescence and on the development of second cancers or post-treatment aging-like syndromes in cancer survivors (cognitive defect, fertility impairment, etc.). In this article, we propose: (1) telomeres of cancer cells are preferential genomic targets of chemotherapies altering chromosome maintenance; (2) telomere functional parameters can be a surrogate marker of chemotherapy sensitivity and toxicity; (3) the use of anti-telomere molecule could greatly enhance the sensitivity to standards chemotherapies.

Keywords

telomere / antineoplasic drugs / conventional chemotherapies

DNA damage response and chemotherapy

The maintenance of DNA integrity is a pivotal aspect of life. However, DNA alterations are common events that occur randomly (i.e., spontaneous hydrolysis, deamination), and are induced by cell division (errors in DNA replication, telomere shortening), by endogenous products (e.g., reactive oxygen species) or upon environmental assaults such as radiations, viral infection or chemical exposure. Cells respond intrinsically to the perception of DNA damage by initiating the DNA damage response (DDR) that leads to cell-cycle arrest and repair attempts. Critical shortening or chromatin alterations of telomeres activate DDR, thereby inducing senescence or apoptosis. These mechanisms correspond to the intrinsic barrier against genome instability and malignancies development.

However, DNA quality control mechanisms eventually fail, leading to accumulation of DNA alterations and excessive telomere shortening, which are associated with the development of cancers. Thus, the increased level of chromosome instability in cancer cells, leading to aneuploidy and gross chromosomal rearrangements, is both a driving force for oncogenesis and can be the Achille’s heel of the disease since many radio- and chemotherapies kill cells by inducing a non-tolerable rate of DNA damage. In addition, senescent cells can be eliminated by natural killer (NK) cells [1] and it was described by Raulet and Gasser that DDR induction by various stresses including chemical stress, UV irradiation or chemotherapy induces the up-regulation of NK cells activating ligands at the surface of the stressed cells leading to NK cells activation and target cells elimination [2]. In addition, it has been shown that some conventional chemotherapies (CTs) (i.e., anthracyclin or oxaliplatin) lead to a better activation of both innate and adaptive immune response (for review [3]). Although the molecular and cellular bases of this immunogenic cell death that is induced by cytotoxic agents are being progressively unravelled, the telomeric status in this context is unknown.

A wealth of published evidence [4-10] shows that telomere stability is more affected than the bulk of the genome by several CT molecules (e.g., cisplatin, spindle poisons as well as anti-topoisomerase I and II and replication inhibitors), suggesting that telomere targeting is a key mechanism of cancer cell killing by CT drugs. These findings open new avenues for innovative combinations of CT drugs, for the use of telomere parameters as surrogate markers for therapy response and toxicity as well as for the introduction of future drugs against telomerase and telomere structural components.

The component of telomeric nucleoprotein complex and its role in cancer

Human telomeres are composed of short, tandemly repeated TTAGGG DNA sequences. A key component of human telosomes is the shelterin complex (See Fig. 1) [11,12], a structure composed of six polypeptides (TRF1, TRF2, RAP1, Tin2, TPP1, and Pot1). Three of the shelterin components recognize directly telomeric DNA; TRF1 and TRF2 bind telomeric DNA duplexes, while Pot1 binds single-stranded 3′ overhangs. The shelterin complex appears to co-localize with nucleosomes. Mammalian telomeric chromatin exhibits characteristics of heterochromatin [13] and triggers telomere position effects (TPE) on transcription [14,15].

Human telomeres are transcribed as UUAGGG-repeats containing TERRA RNAs by RNA polymerase II from promoters located in the subtelomeric region [16-18]. The role of these RNAs in human telomere biology is yet unknown. Determination of the heterochromatinized state of telomeres and regulation of telomerase are attractive possibilities.

Another important feature of human telomeres is the T-loop [19]. T-loops are lasso-like loops joining the very end of telomeres to inner part of the telomeric tract. In a model in vitro system based on the uptake of a single stranded probe by a telomeric plasmid, TRF2 can stimulate such an invasion through the manipulation of the topology of DNA [20]. Telomeric DNA can also fold into intra- or intermolecular structures called guanine quadruplexes or G4 quadruplexes.

In addition, mounting evidence indicates that telomere components also have non-telomeric functions. For example, it has been shown that the catalytic subunit of telomerase acts as a co-factor of the TCF ß-catenin complex involved in the activation of the canonical Wnt pathway through interaction with the chromatin-remodeling factor Brg1 [21]. Moreover, telomeres can exert their influence well beyond the subtelomeric region through the binding of telomere factors to internal chromosomal locations. Indeed, shelterin components can bind and function at a distance from telomeres: (1) Rap1 binds to several sites in the mouse genome [22]; (2) TRF1 and TRF2 can bind to a subset of naturally occurring small stretches of telomeric DNA found interspersed throughout the human genome and named “interstitial telomeric sites” (ITSs) [23,24]. These data indicate that telomeres co-evolved with various mechanisms determining tissue development, homeostasis, and regeneration.

A correct function of telomere seemingly displays antagonistic functions as far as tumorigenesis is concerned [25]. On one hand, overexpression of telomerase in cancer cells is crucial for tumour progression. On the other hand, telomere shortening cooperates with p53 deficiency to favour carcinogenesis in aged mice [26]. By contrast to telomerase, the role of the telomere chromatin in oncogenesis is still poorly understood. TRF2 appears to play an important role in oncogenesis: it is up-regulated in some human tumors [27-29] and has been found to exert powerful oncogenic properties [30,31]. Moreover, TRF2 dosage modulates a cell extrinsic pathway by which tumor cells are eliminated by natural killer (NK) cells [32].

Inhibition of telomerase provides an interesting “universal” strategy for cancer therapy: immunological and pharmacological inhibition of telomerase is currently used in a series of clinical protocols. However, with many but not all telomerase therapeutic approaches, growth arrest has been observed only when telomeres reach a critically short length. An alternative approach, although still poorly developed, is to target key components of telomere structure such as the use of G4 ligands [33].

Known effects of chemotherapy drugs on telomeres in vitro

Telomeres as preferential targets of topoisomerase poisons

Drugs that inhibit topoisomerase activity are widely used in the therapy of different types of cancer. The propensity of telomeres to form T-loops, Holliday junctions and G quadruplexes (G4) as well as the tight attachment to subnuclear structures are expected to block the rotation of telomeric DNA. Hence, transcription and replication may cause important topological problems at chromosome ends [34]. Several recent works support this view and suggest that the resolution of topological problems is at the heart of telomere biology (See Fig. 2).

Topoisomerase I is a constitutive member of the telomeric complex of the linear chromosomes and plasmids in the Streptomyces bacterial species [35]. It is thought to resolve the topological constraints that arise from the association between different telomeres though interactions of covalently bound telomeric complexes. Positive supercoiling at telomeres of another bacterial species, Borrelia, is a driving force that allows resolution of dimer telomeric junctions formed during replication [36]. In unicellular eukaryotes, topoisomerase 2 was shown to play an important role in telomere segregation in the fission yeast [37]. In human cells, the telomeric G4-ligand RHPS4 potentiates the anti-tumour efficacy of TOPO I (topoisomerase I) inhibitors in preclinical models [4,5] and TRF2 protects against the damages caused by topoisomerase 2 poisons [38,39]. Furthermore, topoisomerase 2α is required for telomere protection in a pathway involving TRF2 and its partner Apollo [6]. Interestingly, TRF2 decreases the amount of topoisomerase 2αneeded for a proper end-protection, suggesting a model in which TRF2 relieves the excess of topological stress generated during telomere replication. Since TRF2 is able to wrap DNA in a right-handed manner [20] and to preferentially bind to positively supercoiled DNA substrates [6], it might serve as a topological stress sensor, warranting rapid access to and coordinating the action of multiple enzymatic activities to prevent aberrant topological resolution. Importantly, a reduced amount of topoisomerase 2α or the use of the topoisomerase 2 drug ICRF193 in cancer cells leads to telomere uncapping, revealed by the recruitment of DDR factors at chromosome ends, without increasing global DDR activation, indicating that telomeres are preferential target of topoisomerase 2 inhibition [6].

Therapeutic doses of CT drugs specifically impair telomere function

The antitumour drug cisplatin (cis-[PtCl₂ (NH₃ )₂ ]), which is used in the treatment of several types of cancer, reacts with cellular DNA, preferentially at the N7 positions of guanine bases, leading to 60%-65% of chelates between adjacent guanines. It is accepted that the cytotoxicity of cisplatin is attributed to the formation of the major GG adduct because the tumour response correlates to levels of GG adducts. Therefore, owing to the presence of triple runs of guanines, telomeric DNA is thought to be a preferential target for cisplatin but the effect of cisplatin on telomeres has not been well clarified yet. We recently showed that the binding of TRF2 to telomeric sequences selectively modified by one GG chelate of cisplatin is markedly affected in vitro and in cancer cells [7].

Hydroxyurea (HU) is a chemotherapeutic agent commonly used for various malignancies and hematological disorders, including chronic myelogenous leukemia and sickle cell anemia. In a similar way as cisplatin, chronic, low-level treatment with HU preferentially decreased the rate of telomere DNA synthesis and dissociated TRF2 from telomere DNA [9]. Different from cisplatin and HU, gemcitabine, leads to telomere dysfunction without dissociating TRF2 [40].

Another possible mechanism rendering telomeres more sensitive than the rest of the genome to genotoxic drugs is their inefficient repair leading to a persistent DNA-damage response [41].

Mitotic inhibitors causes telomere uncapping

Prolonged treatment of cancer cells with mitotic inhibitors, including vinblastine, dimethylenastron, velcade and taxol, triggers telomere dysfunction in cancer cells [10].

All these indicate that telomeres are more vulnerable under the treatment of most chemotherapeutic drugs. Further studies are required to elucidate whether telomere functional parameters can be used as surrogate markers of chemotherapy sensitivity and toxicity.

Known effects of chemotherapies on telomeres in patients

Most of the telomere analyses that have been performed in clinical samples in response to CT were focused on telomere length (TL) in blood cells.

Schroder et al. [42] reported that among 17 breast cancer patients who underwent adjuvant CT without stem cell transplantation, the TL of leukocytes 5 months after completion of standard-dose systemic chemotherapy was decreased in 9 patients (52%), with a range between 0.4 and ‒2.2 Kb. The TL of some patients was more affected by chemotherapy than others. Other studies reported an accelerating telomere shortening in blood lineage cells due to the proliferative stress in hematologic malignancies following high-dose CT with hematopoietic stem cell transplantation [43,44] and non-myeloablative CT [45]. Telomere shortening of PBMC could either be secondary to direct damage of bone marrow (BM) cells by cytotoxic drugs (direct effect), or merely the consequence of increased BM cell proliferation after exposure to chemotherapy (indirect effect). Buttiglieri et al. [46] evaluated the initiation of the aging process by chemotherapy on human mesenchymal stem cells (MSCs). MSCs were exposed in vitro to sublethal doses of CT that induce DNA double-stranded breaks (doxorubicin, etoposide). CT induced irreversible TL shortening with reduced clonogenic activity in vitro and altered adipose differentiation. Thus, treatments with CT drugs represent a typical example of premature aging of BM stem cells.

The TL shortening of PBMC in cancer patients undergoing standard-dose CT was associated with good treatment response and neutropenia severity [45]. Short telomeres have been shown to reduce tumor formation in several mouse tumor models [47,26] and a study provided mouse evidence for the existence of a p53-mediated senescence mechanism in response to short telomeres that suppresses tumorigenesis [48].

Overall, it emerges that TL in PBMC may be used as a potential surrogate marker for treatment response or toxicity in different types of malignancies. Whether telomere dysfunction occurs in solid cancer cells following CT is still totally unknown.

Long term effect of chemotherapy on cancer survivors

If PBMC telomeres from cancer survivors who underwent chemotherapy are shorter than those from healthy normal persons, these patients may be at high risk for developing secondary clonal disorders. In fact, Non-Hodgkin’s Lymphoma (NHL) patients have a significant risk for developing secondary malignant neoplasms such as solid tumors, melanoma, Hodgkin’s disease, and cancer of the lung, brain, kidney and bladder [49]. This has been clearly suggested in a HL cohort who underwent CT and in whom CT induced telomere shortening was associated with cytogenetic profiles characterized by the persistence of complex chromosomal rearrangement and clonal aberrations, which was the case of the two cases of second cancer of this cohort [50]. Secondary malignancies have been described among testicular, ovarian and breast cancer survivors. Secondary leukemia has been described in patients treated by anthracyclins for adjuvant/neoadjuvant treatment in breast cancer [51].

Chemotherapy in cancer survivor may also lead to premature aging. It has been shown on fertility with chemotherapy-induced premature ovarian aging [52]. Besides, some trials have reported that chemotherapy may induce cognitive dysfunction [53], a consequence prospectively described for instance among a subset of patients with breast carcinoma treated with adjuvant chemotherapy [54]. Interestingly, these age-related cognitive dysfunctions could be a consequence of TRF2 release from telomeres triggered by some CT drugs [7,9] that might lead a modulation of the expression of neuronal genes [55,23].

Thus, excess malignancies following in cancer survivors represent complications of curative therapies and/or underlying susceptibility states that have etiological and clinical ramifications and need further studies. Since telomere dysfunction contributes to aging process, understanding CT effect on telomere may lead to new clinical perspectives in cancer survivors and aging effect.

Conclusions

It emerges that the peculiar nature of telomeric chromatin renders it more susceptible than the rest of the genome to the action of various CT drugs, addressing the key question of the role of telomere targeting in CT efficiency. Moreover, telomere chromatin changes are associated with early stages of B-cell chronic leukemia (B-CLL), providing the first evidence that specific telomere changes, and not merely telomeric DNA length, could play a role in the natural history of human cancers [56,57].

Therefore, we propose that:

-Telomeres of cancer cells are preferential genomic targets of chemotherapies altering chromosome maintenance;

-Telomere functional parameters can be used as surrogate markers of chemotherapy sensitivity and toxicity;

-The use of anti-telomere molecule could greatly enhance the sensitivity to conventional chemotherapies;

-Telomere dysfunction induced by chemotherapy is involved in the development of second cancers and to post-treatment aging-like syndromes.

References

[1] Xue W, Zender L, Mithing C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007; 445(7128): 656-660

[2] Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 2005; 436(7054): 1186-1190

[3] Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 2011; 8(3): 151-160

[4] Leonetti C, Scarsella M, Riggio G, Rizzo A, Salvati E, D’Incalci M, Staszewsky L, Frapolli R, Stevens MF, Stoppacciaro A, Mottolese M, Antoniani B, Gilson E, Zupi G, Biroccio A. G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors. Clin Cancer Res 2008; 14(22): 7284-7291

[5] Biroccio A, Porru M, Rizzo A, Salvati E, D’Angelo C, Orlandi A, Passeri D, Franceschin M, Stevens MF, Gilson E, Beretta G, Zupi G, Pisano C, Zunino F, Leonetti C. DNA damage persistence as determinant of tumor sensitivity to the combination of Topo I inhibitors and telomere-targeting agents. Clin Cancer Res 2011; 17(8): 2227-2236

[6] Ye J, Lenain C, Bauwens S, Rizzo A, Saint-Léger A, Poulet A, Benarroch D, Magdinier F, Morere J, Amiard S, Verhoeyen E, Britton S, Calsou P, Salles B, Bizard A, Nadal M, Salvati E, Sabatier L, Wu Y, Biroccio A, Londoño-Vallejo A, Giraud-Panis MJ, Gilson E. TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage. Cell 2010; 142(2): 230-242

[7] Ourliac-Garnier I, Poulet A, Charif R, Amiard S, Magdinier F, Rezaï K, Gilson E, Giraud-Panis MJ, Bombard S. Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1. J Biol Inorg Chem 2010; 15(5): 641-654

[8] Lee KH, Rudolph KL, Ju YJ, Greenberg RA, Cannizzaro L, Chin L, Weiler SR, DePinho RA. Telomere dysfunction alters the chemotherapeutic profile of transformed cells. Proc Natl Acad Sci USA 2001; 98(6): 3381-3386

[9] Snyder AR, Zhou J, Deng Z, Lieberman PM. Therapeutic doses of hydroxyurea cause telomere dysfunction and reduce TRF2 binding to telomeres. Cancer Biol Ther 2009; 8(12): 1136-1145

[10] Hayashi MT, Cesare AJ, Fitzpatrick JA, Lazzerini-Denchi E, Karlseder J. A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. Nat Struct Mol Biol 2012; 19(4): 387-394

[11] de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19(18): 2100-2110

[12] Xin H, Liu D, Songyang Z. The telosome/shelterin complex and its functions. Genome Biol 2008; 9(9): 232

[13] Blasco MA. The epigenetic regulation of mammalian telomeres. Nat Rev Genet 2007; 8(4): 299-309

[14] Baur JA, Zou Y, Shay JW, Wright WE. Telomere position effect in human cells. Science 2001; 292(5524): 2075-2077

[15] Koering CE, Pollice A, Zibella MP, Bauwens S, Puisieux A, Brunori M, Brun C, Martins L, Sabatier L, Pulitzer JF, Gilson E. Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep 2002; 3(11): 1055-1061

[16] Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J. Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 2007; 318(5851): 798-801

[17] Schoeftner S, Blasco MA. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol 2008; 10(2): 228-236

[18] Nergadze SG, Farnung BO, Wischnewski H, Khoriauli L, Vitelli V, Chawla R, Giulotto E, Azzalin CM. CpG-island promoters drive transcription of human telomeres. RNA 2009; 15(12): 2186-2194

[19] Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T. Mammalian telomeres end in a large duplex loop (see comments). Cell 1999; 97(4): 503-514

[20] Amiard S, Doudeau M, Pinte S, Poulet A, Lenain C, Faivre-Moskalenko C, Angelov D, Hug N, Vindigni A, Bouvet P, Paoletti J, Gilson E, Giraud-Panis MJ. A topological mechanism for TRF2-enhanced strand invasion. Nat Struct Mol Biol 2007; 14(2): 147-154

[21] Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, Chang W, Meng Z, Cheung P, Ji H, McLaughlin M, Veenstra TD, Nusse R, McCrea PD, Artandi SE. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 2009; 460(7251): 66-72

[22] Martinez P, Thanasoula M, Carlos AR, Gómez-López G, Tejera AM, Schoeftner S, Dominguez O, Pisano DG, Tarsounas M, Blasco MA. Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites. Nat Cell Biol 2010; 12(8): 768-780

[23] Simonet T, Zaragosi LE, Philippe C, Lebrigand K, Schouteden C, Augereau A, Bauwens S, Ye J, Santagostino M, Giulotto E, Magdinier F, Horard B, Barbry P, Waldmann R, Gilson E. The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats. Cell Res 2011; 21(7): 1028-1038

[24] Yang D, Xiong Y, Kim H, He Q, Li Y, Chen R, Songyang Z. Human telomeric proteins occupy selective interstitial sites. Cell Res 2011; 21(7): 1013-1027

[25] Brunori M, Luciano P, Gilson E, Géli V. The telomerase cycle: normal and pathological aspects. J Mol Med (Berl) 2005; 83(4): 244-257

[26] Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 2001; 28(2): 155-159

[27] Klapper W, Krams M, Qian W, Janssen D, Parwaresch R. Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation. Br J Cancer 2003; 89(4): 713-719

[28] Nakanishi K, Kawai T, Kumaki F, Hiroi S, Mukai M, Ikeda E, Koering CE, Gilson E. Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Clin Cancer Res 2003; 9(3): 1105-1111

[29] Bellon M, Datta A, Brown M, Pouliquen JF, Couppie P, Kazanji M, Nicot C. Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia. Int J Cancer 2006; 119(9): 2090-2097

[30] Biroccio A, Rizzo A, Elli R, Koering CE, Belleville A, Benassi B, Leonetti C, Stevens MF, D’Incalci M, Zupi G, Gilson E. TRF2 inhibition triggers apoptosis and reduces tumourigenicity of human melanoma cells. Eur J Cancer 2006; 42(12): 1881-1888

[31] Blanco R, Muñoz P, Flores JM, Klatt P, Blasco MA. Telomerase abrogation dramatically accelerates TRF2-induced epithelial carcinogenesis. Genes Dev 2007; 21(2): 206-220

[32] Biroccio A, Cherfils-Vicini J, Augereau A, Pinte S, Bauwens S, Ye J, Simonet T, Horard B, Jamet K, Cervera L, Mendez-Bermudez A, Poncet D, Grataroli R, de Rodenbeeke CT, Salvati E, Rizzo A, Zizza P, Ricoul M, Cognet C, Kuilman T, Duret H, Lépinasse F, Marvel J, Verhoeyen E, Cosset FL, Peeper D, Smyth MJ, Londoño-Vallejo A, Sabatier L, Picco V, Pages G, Scoazec JY, Stoppacciaro A, Leonetti C, Vivier E, Gilson E. TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells. Nat Cell Biol 2013; 15(7): 818-828

[33] Salvati E, Leonetti C, Rizzo A, Scarsella M, Mottolese M, Galati R, Sperduti I, Stevens MF, D’Incalci M, Blasco M, Chiorino G, Bauwens S, Horard B, Gilson E, Stoppacciaro A, Zupi G, Biroccio A. Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect. J Clin Invest 2007; 117(11): 3236-3247

[34] Gilson E, Géli V. How telomeres are replicated. Nat Rev Mol Cell Biol 2007; 8(10): 825-838

[35] Bao K, Cohen SN. Reverse transcriptase activity innate to DNA polymerase I and DNA topoisomerase I proteins of Streptomyces telomere complex. Proc Natl Acad Sci USA 2004; 101(40): 14361-14366

[36] Bankhead T, Kobryn K, Chaconas G. Unexpected twist: harnessing the energy in positive supercoils to control telomere resolution. Mol Microbiol 2006; 62(3): 895-905

[37] Germe T, Miller K, Cooper JP. A non-canonical function of topoisomerase II in disentangling dysfunctional telomeres. EMBO J 2009; 28(18): 2803-2811

[38] Klapper W, Qian W, Schulte C, Parwaresch R. DNA damage transiently increases TRF2 mRNA expression and telomerase activity. Leukemia 2003; 17(10): 2007-2015

[39] Zhang YW, Zhang ZX, Miao ZH, Ding J. The telomeric protein TRF2 is critical for the protection of A549 cells from both telomere erosion and DNA double-strand breaks driven by salvicine. Mol Pharmacol 2008; 73(3): 824-832

[40] Su CH, Chu WC, Lan KH, Li CP, Chao Y, Lin HC, Lee SD, Tsai YC, Lee WP. Gemcitabine causes telomere attrition by stabilizing TRF2. Eur J Cancer 2012; 48(18): 3465-3474

[41] Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U, Longhese MP, d’Adda di Fagagna F. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 2012; 14(4): 355-365

[42] Schröder CP, Wisman GB, de Jong S, van der Graaf WT, Ruiters MH, Mulder NH, de Leij LF, van der Zee AG, de Vries EG. Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation. Br J Cancer 2001; 84(10): 1348-1353

[43] Rufer N, Brümmendorf TH, Chapuis B, Helg C, Lansdorp PM, Roosnek E. Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation. Blood 2001; 97(2): 575-577

[44] Rocci A, Ricca I, Dellacasa C, Longoni P, Compagno M, Francese R, Lobetti Bodoni C, Manzini P, Caracciolo D, Boccadoro M, Ferrero D, Ladetto M, Carlo-Stella C, Tarella C. Long-term lymphoma survivors following high-dose chemotherapy and autograft: evidence of permanent telomere shortening in myeloid cells, associated with marked reduction of bone marrow hematopoietic stem cell reservoir. Exp Hematol 2007; 35(4): 673-681

[45] Yoon SY, Sung HJ, Park KH, Choi IK, Kim SJ, Oh SC, Seo JH, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS. Telomere length shortening of peripheral blood mononuclear cells in solid-cancer patients undergoing standard-dose chemotherapy might be correlated with good treatment response and neutropenia severity. Acta Haematol 2007; 118(1): 30-37

[46] Buttiglieri S, Ruella M, Risso A, Spatola T, Silengo L, Avvedimento EV, Tarella C. The aging effect of chemotherapy on cultured human mesenchymal stem cells. Exp Hematol 2011; 39(12): 1171-1181

[47] González-Suárez E, Samper E, Flores JM, Blasco MA. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet 2000; 26(1): 114-117

[48] Feldser DM, Greider CW. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 2007; 11(5): 461-469

[49] Mauch PM, Kalish LA, Marcus KC, Coleman CN, Shulman LN, Krill E, Come S, Silver B, Canellos GP, Tarbell NJ. Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin’s disease: long-term analysis of risk factors and outcome. Blood 1996; 87(9): 3625-3632

[50] M’kacher R, Bennaceur-Griscelli A, Girinsky T, Koscielny S, Delhommeau F, Dossou J, Violot D, Leclercq E, Courtier MH, Béron-Gaillard N, Assaf E, Ribrag V, Bourhis J, Feneux D, Bernheim A, Parmentier C, Carde P. Telomere shortening and associated chromosomal instability in peripheral blood lymphocytes of patients with Hodgkin’s lymphoma prior to any treatment are predictive of second cancers. Int J Radiat Oncol Biol Phys 2007; 68(2): 465-471

[51] Smith RE. Risk for the development of treatment-related acute myelocytic leukemia and myelodysplastic syndrome among patients with breast cancer: review of the literature and the National Surgical Adjuvant Breast and Bowel Project experience. Clin Breast Cancer 2003; 4(4): 273-279

[52] Soleimani R, Heytens E, Darzynkiewicz Z, Oktay K. Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise. Aging (Albany NY) 2011; 3(8): 782-793

[53] Deprez S, Amant F, Smeets A, Peeters R, Leemans A, Van Hecke W, Verhoeven JS, Christiaens MR, Vandenberghe J, Vandenbulcke M, Sunaert S. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol 2012; 30(3): 274-281

[54] Quesnel C, Savard J, Ivers H. Cognitive impairments associated with breast cancer treatments: results from a longitudinal study. Breast Cancer Res Treat 2009; 116(1): 113-123

[55] Zhang P, Pazin MJ, Schwartz CM, Becker KG, Wersto RP, Dilley CM, Mattson MP. Nontelomeric TRF2-REST interaction modulates neuronal gene silencing and fate of tumor and stem cells. Curr Biol 2008; 18(19): 1489-1494

[56] Poncet D, Belleville A, t’kint de Roodenbeke C, Roborel de Climens A, Ben Simon E, Merle-Beral H, Callet-Bauchu E, Salles G, Sabatier L, Delic J, Gilson E. Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia. Blood 2008; 111(4): 2388-2391

[57] Augereau A, T’kint de Roodenbeke C, Simonet T, Bauwens S, Horard B, Callanan M, Leroux D, Jallades L, Salles G, Gilson E, Poncet D. Telomeric damage in early stage of chronic lymphocytic leukemia correlates with shelterin dysregulation. Blood 2011; 118(5): 1316-1322

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg