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01-08-2014 | Laboratory Investigation

Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations

Authors: Ahsan S. Farooqi, Rebecca A. Dagg, L. Mi Rim Choi, Jerry W. Shay, C. Patrick Reynolds, Loretta M. S. Lau

Published in: Journal of Neuro-Oncology | Issue 1/2014

Abstract

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere length maintenance mechanism that enables the unlimited proliferation of a subset of cancer cells. Some neuroblastoma (NB) tumors appear to maintain telomere length by activating ALT. Of 40 NB cell lines, we identified four potential ALT cell lines (CHLA-90, SK-N-FI, LA-N-6, and COG-N-291) that were telomerase-negative and had long telomeres (a feature of ALT cells). All four cell lines lacked MYCN amplification and were p53 non-functional upon irradiation. Two of these cell lines (CHLA-90 and SK-N-FI) were positive for C-circles (telomeric DNA circles) and ALT-associated promyelocytic leukemia nuclear bodies, both of which are phenotypic characteristics of ALT. Mutation of ATRX (associated with ALT in tumors) was only found in CHLA-90. Thus, the ALT phenotype in NB may not be limited to tumors with ATRX mutations but is associated with a lack of MYCN amplification and alterations in the p53 pathway.

Blackburn EH (1991) Structure and function of telomeres. Nature 350:569–573PubMedCrossRef

O’Sullivan RJ, Karlseder J (2010) Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 11:171–181PubMedCentralPubMed

Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460PubMedCrossRef

d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198PubMedCrossRef

Greider CW (1998) Telomerase activity, cell proliferation, and cancer. Proc Natl Acad Sci USA 95:90–92PubMedCentralPubMedCrossRef

Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in tetrahymena extracts. Cell 43:405–413PubMedCrossRef

Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015PubMedCrossRef

Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR (1997) Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med 3:1271–1274PubMedCrossRef

Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR (1995) Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 14:4240–4248PubMedCentralPubMed

10.

Cesare AJ, Reddel RR (2010) Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet 11:319–330PubMedCrossRef

11.

Henson JD, Reddel RR (2010) Assaying and investigating alternative lengthening of telomeres activity in human cells and cancers. FEBS Lett 584:3800–3811PubMedCrossRef

12.

Henson JD, Neumann AA, Yeager TR, Reddel RR (2002) Alternative lengthening of telomeres in mammalian cells. Oncogene 21:598–610PubMedCrossRef

13.

Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR (1999) Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res 59:4175–4179PubMed

14.

Nabetani A, Ishikawa F (2011) Alternative lengthening of telomeres pathway: recombination-mediated telomere maintenance mechanism in human cells. J Biochem 149:5–14PubMedCrossRef

15.

Henson JD, Cao Y, Huschtscha LI, Chang AC, Au AY, Pickett HA, Reddel RR (2009) DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity. Nat Biotechnol 27:1181–1185PubMedCrossRef

16.

Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333:425PubMedCentralPubMedCrossRef

17.

Wong LH, McGhie JD, Sim M, Anderson MA, Ahn S, Hannan RD, George AJ, Morgan KA, Mann JR, Choo KH (2010) ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells. Genome Res 20:351–360PubMedCentralPubMedCrossRef

18.

Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, Allis CD (2010) Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci USA 107:14075–14080PubMedCentralPubMedCrossRef

19.

Cheung NK, Zhang J, Lu C, Parker M, Bahrami A, Tickoo SK, Heguy A, Pappo AS, Federico S, Dalton J, Cheung IY, Ding L, Fulton R, Wang J, Chen X, Becksfort J, Wu J, Billups CA, Ellison D, Mardis ER, Wilson RK, Downing JR, Dyer MA (2012) Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 307:1062–1071PubMedCentralPubMedCrossRef

20.

Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, van Noesel MM, Ora I, Santo EE, Caron HN, Westerhout EM, Versteeg R (2012) Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483:589–593PubMedCrossRef

21.

Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, Carter SL, Cibulskis K, Hanna M, Kiezun A, Kim J, Lawrence MS, Lichenstein L, McKenna A, Pedamallu CS, Ramos AH, Shefler E, Sivachenko A, Sougnez C, Stewart C, Ally A, Birol I, Chiu R, Corbett RD, Hirst M, Jackman SD, Kamoh B, Khodabakshi AH, Krzywinski M, Lo A, Moore RA, Mungall KL, Qian J, Tam A, Thiessen N, Zhao Y, Cole KA, Diamond M, Diskin SJ, Mosse YP, Wood AC, Ji L, Sposto R, Badgett T, London WB, Moyer Y, Gastier-Foster JM, Smith MA, Auvil JM, Gerhard DS, Hogarty MD, Jones SJ, Lander ES, Gabriel SB, Getz G, Seeger RC, Khan J, Marra MA, Meyerson M, Maris JM (2013) The genetic landscape of high-risk neuroblastoma. Nat Genet 45:279–284PubMedCentralPubMedCrossRef

22.

Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. Lancet 369:2106–2120PubMedCrossRef

23.

Onitake Y, Hiyama E, Kamei N, Yamaoka H, Sueda T, Hiyama K (2009) Telomere biology in neuroblastoma: telomere binding proteins and alternative strengthening of telomeres. J Pediatr Surg 44:2258–2266PubMedCrossRef

24.

Lundberg G, Sehic D, Lansberg JK, Ora I, Frigyesi A, Castel V, Navarro S, Piqueras M, Martinsson T, Noguera R, Gisselsson D (2011) Alternative lengthening of telomeres-An enhanced chromosomal instability in aggressive non-MYCN amplified and telomere elongated neuroblastomas. Genes Chromosomes Cancer. doi:10.1002/gcc.20850 PubMed

25.

Ambros PF, Ambros IM, Brodeur GM, Haber M, Khan J, Nakagawara A, Schleiermacher G, Speleman F, Spitz R, London WB, Cohn SL, Pearson AD, Maris JM (2009) International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer 100:1471–1482PubMedCentralPubMedCrossRef

26.

Reynolds CP, Tomayko MM, Donner L, Helson L, Seeger RC, Triche TJ, Brodeur GM (1988) Biological classification of cell lines derived from human extra-cranial neural tumors. Prog Clin Biol Res 271:291–306PubMed

27.

Keshelava N, Seeger RC, Groshen S, Reynolds CP (1998) Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Res 58:5396–5405PubMed

28.

Keshelava N, Zuo JJ, Chen P, Waidyaratne SN, Luna MC, Gomer CJ, Triche TJ, Reynolds CP (2001) Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines. Cancer Res 61:6185–6193PubMed

29.

Masters JR, Thomson JA, Daly-Burns B, Reid YA, Dirks WG, Packer P, Toji LH, Ohno T, Tanabe H, Arlett CF, Kelland LR, Harrison M, Virmani A, Ward TH, Ayres KL, Debenham PG (2001) Short tandem repeat profiling provides an international reference standard for human cell lines. Proc Natl Acad Sci USA 98:8012–8017PubMedCentralPubMedCrossRef

30.

Lau LM, Dagg RA, Henson JD, Au AY, Royds JA, Reddel RR (2013) Detection of alternative lengthening of telomeres by telomere quantitative PCR. Nucleic Acids Res 41:e34PubMedCentralPubMedCrossRef

31.

Mosse YP, Diskin SJ, Wasserman N, Rinaldi K, Attiyeh EF, Cole K, Jagannathan J, Bhambhani K, Winter C, Maris JM (2007) Neuroblastomas have distinct genomic DNA profiles that predict clinical phenotype and regional gene expression. Genes Chromosomes Cancer 46:936–949PubMedCrossRef

32.

Perrem K, Colgin LM, Neumann AA, Yeager TR, Reddel RR (2001) Coexistence of alternative lengthening of telomeres and telomerase in hTERT-transfected GM847 cells. Mol Cell Biol 21:3862–3875PubMedCentralPubMedCrossRef

33.

Keshelava N, Tsao-Wei D, Reynolds CP (2003) Pyrazoloacridine is active in multidrug-resistant neuroblastoma cell lines with nonfunctional p53. Clin Cancer Res 9:3492–3502PubMed

34.

Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL, Choti MA, Velculescu VE, Diaz LA Jr, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331:1199–1203PubMedCentralPubMedCrossRef

35.

Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:e47PubMedCentralPubMedCrossRef

36.

Binz N, Shalaby T, Rivera P, Shin-ya K, Grotzer MA (2005) Telomerase inhibition, telomere shortening, cell growth suppression and induction of apoptosis by telomestatin in childhood neuroblastoma cells. Eur J Cancer 41:2873–2881PubMedCrossRef

37.

Schmidt ML, Lukens JN, Seeger RC, Brodeur GM, Shimada H, Gerbing RB, Stram DO, Perez C, Haase GM, Matthay KK (2000) Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children’s Cancer Group study. J Clin Oncol 18:1260–1268PubMed

38.

Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J, de Lange T, De S, Petrini JH, Sung PA, Jasin M, Rosenbluh J, Zwang Y, Weir BA, Hatton C, Ivanova E, Macconaill L, Hanna M, Hahn WC, Lue NF, Reddel RR, Jiao Y, Kinzler K, Vogelstein B, Papadopoulos N, Meeker AK (2012) Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet 8:e1002772PubMedCentralPubMedCrossRef

39.

Carr J, Bell E, Pearson AD, Kees UR, Beris H, Lunec J, Tweddle DA (2006) Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse. Cancer Res 66:2138–2145PubMedCrossRef

40.

Carr-Wilkinson J, O’Toole K, Wood KM, Challen CC, Baker AG, Board JR, Evans L, Cole M, Cheung NK, Boos J, Kohler G, Leuschner I, Pearson AD, Lunec J, Tweddle DA (2010) High frequency of p53/MDM2/p14ARF pathway abnormalities in relapsed neuroblastoma. Clin Cancer Res 16:1108–1118PubMedCentralPubMedCrossRef

41.

Van Maerken T, Vandesompele J, Rihani A, De Paepe A, Speleman F (2009) Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis. Cell Death Differ 16:1563–1572PubMedCrossRef

42.

Thompson PM, Maris JM, Hogarty MD, Seeger RC, Reynolds CP, Brodeur GM, White PS (2001) Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma. Cancer Res 61:679–686PubMed

43.

Salvioli S, Bonafe M, Barbi C, Storci G, Trapassi C, Tocco F, Gravina S, Rossi M, Tiberi L, Mondello C, Monti D, Franceschi C (2005) p53 codon 72 alleles influence the response to anticancer drugs in cells from aged people by regulating the cell cycle inhibitor p21WAF1. Cell Cycle 4:1264–1271PubMedCrossRef

44.

Hiyama E, Hiyama K, Yokoyama T, Matsuura Y, Piatyszek MA, Shay JW (1995) Correlating telomerase activity levels with human neuroblastoma outcomes. Nat Med 1:249–255PubMedCrossRef

45.

Poremba C, Willenbring H, Hero B, Christiansen H, Schafer KL, Brinkschmidt C, Jurgens H, Bocker W, Dockhorn-Dworniczak B (1999) Telomerase activity distinguishes between neuroblastomas with good and poor prognosis. Ann Oncol 10:715–721PubMedCrossRef

46.

Poremba C, Scheel C, Hero B, Christiansen H, Schaefer KL, Nakayama J, Berthold F, Juergens H, Boecker W, Dockhorn-Dworniczak B (2000) Telomerase activity and telomerase subunits gene expression patterns in neuroblastoma: a molecular and immunohistochemical study establishing prognostic tools for fresh-frozen and paraffin-embedded tissues. J Clin Oncol 18:2582–2592PubMed

47.

Bryan TM, Marusic L, Bacchetti S, Namba M, Reddel RR (1997) The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit. Hum Mol Genet 6:921–926PubMedCrossRef

Title: Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations
Authors: Ahsan S. Farooqi
Rebecca A. Dagg
L. Mi Rim Choi
Jerry W. Shay
C. Patrick Reynolds
Loretta M. S. Lau
Publication date: 01-08-2014
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 1/2014
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-014-1456-8

At a glance: The STEP trials

Springer Medicine

Alternative lengthening of telomeres in neuroblastoma cell lines is associated with a lack of MYCN genomic amplification and with p53 pathway aberrations

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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