Loss of function of Atrx leads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma.
| العنوان: | Loss of function of Atrx leads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma. |
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| المؤلفون: | Pierpoint M; Duke of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada., Floyd W; Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Wisdom AJ; Harvard Radiation Oncology Program, Harvard University, Boston, MA, 02115, USA., Luo L; Duke Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA., Ma Y; Duke Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA., Waitkus MS; Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA.; Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA.; The Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC 27710, USA., Kirsch DG; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.; Department of Radiation Oncology, University of Toronto, Toronto, ON M5G 2M9, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 06. Date of Electronic Publication: 2023 Nov 06. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of telomeres (ALT). In this work, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice which displays multiple molecular features of ALT activation after CRISPR/Cas9 introduction of oncogenic Kras G12D and loss of function mutations of Trp53 and Atrx . In this model, we demonstrate that the loss of Atrx contributes to the development of ALT in an autochthonous tumor, and this process occurs independently of telomerase function by variation of mTR alleles. Furthermore, we find that telomere shortening from the loss of telomerase leads to higher chromosomal instability while loss of Atrx and activation of ALT lead to an increase in telomeric instability, telomere sister chromatid exchange, c-circle production, and formation of ALT-associated promyelocytic leukemia bodies (APBs). The development of this primary mouse model of ALT could enable future investigations into therapeutic vulnerabilities of ALT activation and its mechanism of action. Competing Interests: DGK is a cofounder of Xrad Therapeutics, which is developing radiosensitizers, and serves on the Scientific Advisory Board of Lumicell, which is commercializing intraoperative imaging technology. DGK is a coinventor on patents for radiosensitizers and an intraoperative imaging device. DGK also receives funding for a clinical trial from a Stand Up To Cancer (SU2C) Catalyst Research Grant with support from Merck. Amgen provided the mouse variant TVEC used in this study. The laboratory of DGK currently receives funding or reagents from Xrad Therapeutics, Merck, Bristol-Myers Squibb, Varian Medical Systems, and Calithera, but these did not support the research described in this manuscript. |
| References: | PLoS One. 2018 Sep 18;13(9):e0204159. (PMID: 30226859) J Clin Invest. 2023 Jul 3;133(13):. (PMID: 37200088) Mod Pathol. 2015 Dec;28(12):1545-54. (PMID: 26428317) Clin Cancer Res. 2005 Jan 1;11(1):217-25. (PMID: 15671549) Cancer Res. 1999 Sep 1;59(17):4175-9. (PMID: 10485449) Nat Commun. 2023 Feb 20;14(1):939. (PMID: 36805596) Genes Chromosomes Cancer. 2004 Oct;41(2):155-62. (PMID: 15287028) Cancer Res. 2004 Apr 1;64(7):2324-7. (PMID: 15059879) Mod Pathol. 2015 Aug;28(8):1064-73. (PMID: 26022452) EMBO J. 2019 Oct 1;38(19):e96659. (PMID: 31454099) Nat Commun. 2021 Feb 17;12(1):1097. (PMID: 33597549) Sci Transl Med. 2016 Mar 2;8(328):328ra28. (PMID: 26936505) Nat Commun. 2018 Jan 10;9(1):144. (PMID: 29321523) Nat Med. 2007 Aug;13(8):992-7. (PMID: 17676052) PLoS Genet. 2012;8(7):e1002772. (PMID: 22829774) Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12606-11. (PMID: 12193655) Eur J Cancer. 1997 Apr;33(5):787-91. (PMID: 9282118) Science. 1998 Jan 16;279(5349):349-52. (PMID: 9454332) Oncotarget. 2015 Jun 30;6(18):16543-58. (PMID: 26001292) PLoS Genet. 2009 Jan;5(1):e1000357. (PMID: 19180191) Nucleic Acids Res. 2000 Nov 15;28(22):4474-8. (PMID: 11071935) Nat Commun. 2015 Jul 06;6:7538. (PMID: 26143912) Curr Protoc Cytom. 2015 Jul 01;73:12.40.1-12.40.31. (PMID: 26132175) Am J Pathol. 2011 Oct;179(4):1608-15. (PMID: 21888887) Nat Biotechnol. 2009 Dec;27(12):1181-5. (PMID: 19935656) Cell. 1997 Oct 3;91(1):25-34. (PMID: 9335332) BMC Cancer. 2019 Mar 14;19(1):232. (PMID: 30871494) J Clin Invest. 2013 May;123(5):2049-63. (PMID: 23563309) Cell. 2012 Feb 17;148(4):651-63. (PMID: 22341440) Proc Natl Acad Sci U S A. 1995 May 23;92(11):4818-22. (PMID: 7761406) PLoS Biol. 2020 Jan 2;18(1):e3000594. (PMID: 31895940) Nat Med. 1997 Nov;3(11):1271-4. (PMID: 9359704) Mol Cell Biol. 2000 Jun;20(11):4115-27. (PMID: 10805753) Cell. 1982 May;29(1):245-55. (PMID: 6286143) Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3591-6. (PMID: 11904421) Mol Cell Biol. 2011 Jun;31(12):2369-79. (PMID: 21464209) Nat Commun. 2017 Jul 10;8:15999. (PMID: 28691711) Cytometry. 1999 Aug 1;36(4):267-78. (PMID: 10404142) Mol Cancer Res. 2019 Dec;17(12):2480-2491. (PMID: 31611308) |
| معلومات مُعتمدة: | R35 CA197616 United States CA NCI NIH HHS |
| تواريخ الأحداث: | Date Created: 20231121 Latest Revision: 20231207 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC10659347 |
| DOI: | 10.1101/2023.11.06.565874 |
| PMID: | 37986934 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.11.06.565874 |
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