Author: Dagg RA1, Pickett HA2, Neumann AA3, Napier CE3, Henson JD4, Teber ET5, Arthur JW5, Reynolds CP6, Murray J7, Haber M7, Sobinoff AP2, Lau LMS8, Reddel RR9
Affiliation: <sup>1</sup>Children's Cancer Research Unit, The Children's Hospital at Westmead, University of Sydney, Westmead, NSW 2145, Australia.
<sup>2</sup>Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
<sup>3</sup>Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
<sup>4</sup>Cancer Cell Immortality Group, Adult Cancer Program, Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2052, Australia.
<sup>5</sup>Bioinformatics Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
<sup>6</sup>Cancer Center, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Internal Medicine, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
<sup>7</sup>Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, NSW 2031, Australia.
<sup>8</sup>Children's Cancer Research Unit, The Children's Hospital at Westmead, University of Sydney, Westmead, NSW 2145, Australia; Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
<sup>9</sup>Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia. Electronic address: rreddel@cmri.org.au.
Conference/Journal: Cell Rep.
Date published: 2017 Jun 20
Other:
Volume ID: 19 , Issue ID: 12 , Pages: 2544-2556 , Special Notes: doi: 10.1016/j.celrep.2017.05.087. , Word Count: 173
Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative. As serial samples of human tumors cannot usually be obtained to monitor telomere length changes, it has previously been impossible to determine whether tumors are truly TLM-deficient, there is a previously unrecognized TLM, or the assay results are false-negative. Here, we show that a subset of high-risk neuroblastomas (with ∼50% 5-year mortality) lacked significant TLM activity. Cancer cells derived from these highly aggressive tumors initially had long telomeres and proliferated for >200 population doublings with ever-shorter telomeres. This indicates that prevention of telomere shortening is not always required for oncogenesis, which has implications for inhibiting TLMs for cancer therapy.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS: alternative lengthening of telomeres; ever-shorter telomeres; neuroblastoma; telomerase; telomeres
PMID: 28636942 DOI: 10.1016/j.celrep.2017.05.087