Targeting ALT: The role of alternative lengthening of telomeres in pathogenesis and prevention of cancer

Published:October 16, 2007DOI:https://doi.org/10.1016/j.ctrv.2007.08.006

      Summary

      Telomere shortening in the course of cell divisions plays an important role in both suppression and pathogenesis of cancer. Telomere maintenance mechanisms such as telomerase and alternative lengthening of telomeres (ALT) are essential for long-term tumor growth. Consequently, interdiction of telomere lengthening has been proposed as an anti-cancer treatment but requires insight in the genes and pathways involved.
      In this article, the molecular and functional details of ALT are reviewed, and proposed next steps towards a therapy aimed at preventing ALT in human cancers are described.

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      References

        • Olovnikov A.M.
        A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon.
        J Theor Biol. 1973; 41: 181-190
        • Wright W.E.
        • Shay J.W.
        The two-stage mechanism controlling cellular senescence and immortalization.
        Exp Gerontol. 1992; 27: 383-389
        • Henson J.D.
        • Neumann A.A.
        • Yeager T.R.
        • Reddel R.R.
        Alternative lengthening of telomeres in mammalian cells.
        Oncogene. 2002; 21: 598-610
      1. White LK, Wright WE, Shay JW. Telomerase inhibitors. Trends Biotechnol 200; 19(3):114–20.

        • de Grey A.D.N.J.
        • Campbell F.C.
        • Dokal I.
        • Fairbairn L.J.
        • Graham G.J.
        • Jahoda C.A.B.
        • et al.
        Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers.
        Ann NY Acad Sci. 2004; 1019: 147-170
        • Bryan T.M.
        • Reddel R.R.
        Telomere dynamics and telomerase activity in in vitro immortalised human cells.
        Eur J Cancer. 1997; 33: 767-773
        • Perrem K.
        • Bryan T.M.
        • Englezou A.
        • Hackl T.
        • Moy E.A.
        • Reddel R.R.
        Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids.
        Oncogene. 1999; 18: 3383-3390
        • Grobelny J.V.
        • Kulp-McEliece M.
        • Broccoli D.
        Effects of reconstitution of telomerase activity on telomere maintenance by the alternative lengthening of telomeres (ALT) pathway.
        Human Mol Gen. 2001; 10: 1953-1961
        • Cerone M.A.
        • Londono-Vallejo J.A.
        • Bacchetti S.
        Telomere maintenance by telomerase and by recombination can coexist in human cells.
        Human Mol Gen. 2001; 10: 1945-1952
        • Perrem K.
        • Colgin L.M.
        • Neumann A.A.
        • Yeager T.R.
        • Reddel R.R.
        Coexistence of alternative lengthening of telomeres and telomerase in hTERT-transfected GM847 Cells.
        Mol Cell Biol. 2001; 21: 3862-3875
        • Yeager T.R.
        • Neumann A.A.
        • Englezou A.
        • Huschtscha L.I.
        • Noble J.R.
        • Reddel R.R.
        Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body.
        Cancer Res. 1999; 59: 4175-4179
        • Nabetani A.
        • Yokoyama O.
        • Ishikawa F.
        Localization of hRad9, hHus1, hRad1, and hRad17 and caffeine-sensitive DNA replication at the alternative lengthening of telomeres-associated promyelocytic leukemia body.
        J Biol Chem. 2004; 279: 25849-25857
        • Grobelny J.V.
        • Godwin A.K.
        • Broccoli D.
        ALT-associated PML bodies are present in viable cells and are enriched incells in the G2/M phase of the cell cycle.
        J Cell Sci. 2000; 113: 4577-4585
        • Fasching C.L.
        • Bower K.
        • Reddel R.R.
        Telomerase-independent telomere length maintenance in the absence of alternative lengthening of telomeres-associated promyelocytic leukemia bodies.
        Cancer Res. 2005; 65: 2722-2729
        • Bechter O.E.
        • Shay J.W.
        • Wright W.E.
        The frequency of homologous recombination in human ALT cells.
        Cell Cycle. 2004; 3: 547-549
        • Bailey S.M.
        • Brenneman M.A.
        • Goodwin E.H.
        Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells.
        Nucleic Acids Res. 2004; 32: 3743-3751
        • Dunham M.A.
        • Neumann A.A.
        • Fasching C.L.
        • Reddel R.R.
        Telomere maintenance by recombination in human cells.
        Nature Gen. 2000; 26: 447-450
        • Bechter O.E.
        • Zou Y.
        • Shay J.W.
        • Wright W.E.
        Homologous recombination in human telomerase-positive and ALT cells occurs with the same frequency.
        EMBO Rep. 2003; 4: 1138-1143
        • Londono-Vallejo J.A.
        • Der-Sarkissian H.
        • Cazes L.
        • Bacchetti S.
        • Reddel R.R.
        Alternative lengthening of telomeres is characterized by high rates of telomeric exchange.
        Cancer Res. 2004; 64: 2324-2327
        • Bechter O.E.
        • Zou Y.
        • Walker W.
        • Wright W.E.
        • Shay J.W.
        Telomeric recombination in mismatch repair deficient human colon cancer cells after telomerase inhibition.
        Cancer Res. 2004; 64: 3444-3451
        • Jiang W.Q.
        • Zhong Z.H.
        • Henson J.D.
        • Reddel R.R.
        Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference.
        Oncogene. 2005; (Advance Online Publication 5 February)
        • Stavropoulos D.J.
        • Bradshaw P.S.
        • Li X.
        • Pasic I.
        • Truong K.
        • Ikura M.
        • et al.
        The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis.
        Human Mol Gen. 2002; 11: 3135-3144
        • Lillard-Wetherell K.
        • Machwe A.
        • Langland G.T.
        • Combs K.A.
        • Behbehani G.K.
        • Schonberg S.A.
        • et al.
        Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2.
        Human Mol Gen. 2004; 13: 1919-1932
        • Opresko P.L.
        • Otterlei M.
        • Graakjaer J.
        • Bruheim P.
        • Dawut L.
        • Kolvraa S.
        • et al.
        The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2.
        Mol Cell. 2004; 14: 763-774
        • Celli G.B.
        • Denchi E.L.
        • de Lange T.
        Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination.
        Nat Cell Biol. 2006; 8: 855-890
        • Tanaka H.
        • Mendonca M.S.
        • Bradshaw P.S.
        • Hoelz D.J.
        • Malkas L.H.
        • Meyn M.S.
        • et al.
        DNA damage-induced phosphorylation of the human telomere-associated protein TRF2.
        Proc Natl Acad Sci USA. 2005; 102: 15539-15544
        • Muntoni A.
        • Reddel R.R.
        The first molecular details of ALT in human tumor cells.
        Human Mol Gen. 2005; 14: 191-196
        • Martens U.M.
        • Chavez E.A.
        • Poon S.S.
        • Schmoor C.
        • Lansdorp P.M.
        Accumulation of short telomeres in human fibroblasts prior to replicative senescence.
        Exp Cell Res. 2000; 256: 291-299
        • Natarajan S.
        • Groff-Vindman C.
        • McEachern M.J.
        Factors influencing the recombinational expansion and spread of telomeric tandem arrays in Kluyveromyces lactis.
        Eukaryot Cell. 2003; 2: 1115-1127
        • Tomaska L.
        • Nosek J.
        • Makhov A.M.
        • Pastorakova A.
        • Griffith J.D.
        Extragenomic double-stranded DNA circles in yeast with linear mitochondrial genomes: potential involvement in telomere maintenance.
        Nucleic Acids Res. 2000; 28: 4479-4487
        • Compton S.A.
        • Choi J.H.
        • Cesare A.J.
        • Ozgur S.
        • Griffith J.D.
        Xrcc3 and Nbs1 are required for the production of extrachromosomal telomeric circles in human alternative lengthening of telomere cells.
        Cancer Res. 2007; 67: 1513-1519
        • Wang R.C.
        • Smogorzewska A.
        • de Lange T.
        Homologous recombination generates t-loop-sized deletions at human telomeres.
        Cell. 2004; 119: 355-368
        • Ibanez de Caceres I.
        • Frolova N.
        • Varkonyi R.J.
        • Dulaimi E.
        • Meropol N.J.
        • Broccoli D.
        • et al.
        Telomerase is frequently activated in tumors with microsatellite instability.
        Cancer Biol Ther. 2004; 3: 289-292
        • Scheel C.
        • Poremba C.
        Telomere lengthening in telomerase-negative cells: the ends are coming together.
        Virchows Arch. 2002; 440: 573-582
        • Hakin-Smith V.
        • Jellinek D.A.
        • Levy D.
        • Carroll T.
        • Teo M.
        • Timperley W.R.
        • et al.
        Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme.
        Lancet. 2003; 361: 836-838
        • Ulaner G.A.
        • Huang H.Y.
        • Otero J.
        • Zhao Z.
        • Ben-Porat L.
        • Satagopan J.M.
        • et al.
        Absence of a telomere maintenance mechanism as a favorable prognostic factor in patients with osteosarcoma.
        Cancer Res. 2003; 63: 1759-1763
        • Sharpless N.E.
        • DePinho R.A.
        p53. Good cop/bad cop.
        Cell. 2002; 110: 9-12
        • Razak Z.R.A.
        • Varkonyi R.J.
        • Kulp-McEliece M.
        • Caslini C.
        • Testa J.R.
        • Murphy M.E.
        • et al.
        p53 differentially inhibits cell growth depending on the mechanism of telomere maintenance.
        Mol Cell Biol. 2004; 24: 5967-5977
        • Chen Y.J.
        • Hakin-Smith V.
        • Teo M.
        • Xinarianos G.E.
        • Jellinek D.A.
        • Carroll T.
        • et al.
        Association of mutant TP53 with ALT and favorable prognosis in glioma.
        Cancer Res. 2006; 66: 6473-6476
        • Sood A.K.
        • Coffin J.
        • Jabbari S.
        • Buller R.E.
        • Hendrix M.J.C.
        • Klingelhutz A.
        p53 null mutations are associated with a telomerase negative phenotype in ovarian carcinoma.
        Cancer Biol Ther. 2002; 1: 511-517
        • Bossi G.
        • Sacchi A.
        Restoration of wild-type p53 function in human cancer: relevance for tumor therapy.
        Head Neck. 2007; 29: 272-284
        • Mai S.
        • Garini Y.
        The significance of telomeric aggregates in the interphase nuclei of tumor cells.
        J Cell Biochem. 2006; 97: 904-915
        • Maser R.S.
        • DePinho R.A.
        Connecting chromosomes, crisis and cancer.
        Science. 2002; 297: 565-569
        • Sharpless N.E.
        • De Pinho R.A.
        Telomeres, stem cells, senescence, and cancer.
        J Clin Invest. 2004; 113: 160-168
        • Greenberg R.A.
        • Chin L.
        • Femino A.
        • Lee K.H.
        • Gottlieb G.J.
        • Singer R.H.
        • et al.
        Short dysfunctional telomeres impair tumorigenesis in the INK4a(Δ2/3) cancer-prone mouse.
        Cell. 1999; 14: 515-525
        • Rudolph K.L.
        • Chang S.
        • Lee H.W.
        • Blasco M.
        • Gottlieb G.J.
        • Greider C.W.
        • et al.
        Longevity, stress response, and cancer in aging telomerase-deficient mice.
        Cell. 2001; 96: 701-712
        • Artandi S.E.
        • Chang S.
        • Lee S.L.
        • Alson S.
        • Gottlieb G.J.
        • Chin L.
        • et al.
        Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.
        Nature. 2000; 406: 641-645
        • O’Hagan R.C.
        • Chang S.
        • Maser R.S.
        • Mohan R.
        • Artandi S.E.
        • Chin L.
        • et al.
        Telomere dysfunction provokes regional amplification and deletion in cancer genomes.
        Cancer Cell. 2002; 2: 149-155
        • Seger R.Y.
        • Garcia-Cao M.
        • Piccinin S.
        • Cunsolo C.L.
        • Doglioni C.
        • Blasco M.A.
        • et al.
        Transformation of normal human cells in the absence of telomerase activation.
        Cancer Cell. 2002; 2: 401-413
        • Farazi P.A.
        • Glickman J.
        • Jiang S.
        • Yu A.
        • Rudolph K.L.
        • DePinho R.A.
        Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma.
        Cancer Res. 2003; 63: 5021-5027
        • Chang S.
        • Khoo C.M.
        • Naylor M.L.
        • Maser R.S.
        • DePinho R.A.
        Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression.
        Genes Develop. 2003; 17: 88-100
        • Gupta J.
        • Han L.P.
        • Wang P.
        • Gallie B.L.
        • Bacchetti S.
        Development of retinoblastoma in the absence of telomerase activity.
        J Natl Cancer Inst. 1996; 88: 1152-1157
        • Ulaner G.A.
        • Hoffman A.R.
        • Otero J.
        • Huang H.Y.
        • Zhao Z.
        • Mazumdar M.
        • et al.
        Divergent patterns of telomere maintenance mechanisms among human sarcomas: sharply contrasting prevalence of the alternative lengthening of telomeres mechanism in Ewing’s sarcomas and osteosarcomas.
        Genes, Chromosomes Cancer. 2004; 41: 155-162
        • Johnson J.E.
        • Varkonyi R.J.
        • Schwalm J.
        • Cragle R.
        • Klein-Szanto A.
        • Patchefsky A.
        • et al.
        Multiple mechanisms of telomere maintenance exist in liposarcomas.
        Clin Cancer Res. 2005; 11: 5347-5355
        • Kumakura S.I.
        • Tsutsui T.W.
        • Yagisawa J.
        • Barrett J.C.
        • Tsutsui T.
        Reversible conversion of immortal human cells from telomerase-positive to telomerase-negative cells.
        Cancer Res. 2005; 65: 2778-2786
        • Gan Y.
        • Mo Y.
        • Johnston J.
        • Lu J.
        • Wientjes M.G.
        • Au J.L.S.
        Telomere maintenance in telomerase-positive human ovarian SKOV-3 cells cannot be retarded by complete inhibition of telomerase.
        FEBS Lett. 2002; 524: 10-14
        • Brachner A.
        • Sasgary S.
        • Pirker C.
        • Rodgarkia C.
        • Mikula M.
        • Mikulits W.
        • et al.
        Telomerase- and alternative telomere lengthening–independent telomere stabilization in a metastasis-derived human non-small cell lung cancer cell line: effect of ectopic hTERT.
        Cancer Res. 2006; 66: 3584-3592
        • Cerone M.A.
        • Autexier C.
        • Londono-Vallejo J.A.
        • Bacchetti S.
        A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT.
        Oncogene. 2005; 24: 7893-7901
        • Argilla D.
        • Chin K.
        • Singh M.
        • Hodgson J.G.
        • Bosenberg M.
        • Ortiz de Solorzano C.
        • et al.
        Absence of telomerase and shortened telomeres have minimal effects on skin and pancreatic carcinogenesis elicited by viral oncogenes.
        Cancer Cell. 2004; 6: 373-385
        • Marciniak R.A.
        • Cavazos D.
        • Montellano R.
        • Chen Q.
        • Guarente L.
        • Johnson F.B.
        A novel telomere structure in a human alternative lengthening of telomeres cell line.
        Cancer Res. 2005; 65: 2730-2737
        • Tsai H.J.
        • Huang W.H.
        • Li T.K.
        • Tsai Y.L.
        • Wu K.J.
        • Tseng S.F.
        • et al.
        Involvement of topoisomerase III in telomere–telomere recombination.
        J Biol Chem. 2006; 281: 13717-13723
        • Silverman J.
        • Takai H.
        • Buonomo S.B.C.
        • Eisenhaber F.
        • de Lange T.
        Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint.
        Genes Develop. 2004; 18: 2108-2119
        • Jiang W.Q.
        • Zhong Z.H.
        • Henson J.D.
        • Neumann A.A.
        • Chang A.C.M.
        • Reddel R.R.
        Suppression of alternative lengthening of telomeres by Sp100-mediated sequestration of the MRE11/RAD50/NBS1 complex.
        Mol Cell Biol. 2005; 25: 2708-2721