{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:56:26Z","timestamp":1790207786354,"version":"4.1.0"},"reference-count":28,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Geron (United States)","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}]},{"DOI":"10.13039\/100016935","name":"Lisa Dean Moseley Foundation","doi-asserted-by":"publisher","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}],"id":[{"id":"10.13039\/100016935","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leukemia Research Foundation of Delaware","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103446"],"award-info":[{"award-number":["P20GM103446"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016610","name":"Andrew McDonough B+ Foundation","doi-asserted-by":"publisher","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}],"id":[{"id":"10.13039\/100016610","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012465","name":"Nemours Foundation","doi-asserted-by":"publisher","award":["unnumbered"],"award-info":[{"award-number":["unnumbered"]}],"id":[{"id":"10.13039\/100012465","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Acute myeloid leukemia (AML) in children remains deadly, despite the use of maximally intensive therapy. Because leukemia stem cells (LSCs) significantly contribute to chemoresistance and relapse, therapies that specifically target the LSCs are likely to be more beneficial in improving outcome. LSCs are known to have high telomerase activity and telomerase activity is negatively correlated with survival in pediatric AML. We evaluated the preclinical efficacy of imetelstat, an oligonucleotide inhibitor of telomerase activity in patient-derived xenograft (PDX) lines of pediatric AML. Imetelstat treatment significantly increased apoptosis\/death of the LSC population in a dose-dependent manner in six pediatric AML PDX lines ex vivo, while it had limited activity on the stem cell population in normal bone marrow specimens. These results were validated in vivo in two distinct PDX models wherein imetelstat as single agent or in combination with chemotherapy greatly reduced the LSC percentage and prolonged median survival. Imetelstat combination with DNA hypomethylating agent azacitidine was also beneficial in extending survival. Secondary transplantation experiments showed delayed engraftment and improved survival of mice receiving imetelstat-treated cells, confirming the diminished LSC population. Thus, our data suggest that imetelstat represents an effective therapeutic strategy for pediatric AML.<\/jats:p>","DOI":"10.3390\/jcm11071923","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T21:28:39Z","timestamp":1648675719000},"page":"1923","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4162-3004","authenticated-orcid":false,"given":"Sonali P.","family":"Barwe","sequence":"first","affiliation":[{"name":"Nemours Centers for Childhood Cancer Research and Cancer & Blood Disorders, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Huang","sequence":"additional","affiliation":[{"name":"Geron Corporation, Parsippany, NJ 07054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward Anders","family":"Kolb","sequence":"additional","affiliation":[{"name":"Nemours Centers for Childhood Cancer Research and Cancer & Blood Disorders, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0465-578X","authenticated-orcid":false,"given":"Anilkumar","family":"Gopalakrishnapillai","sequence":"additional","affiliation":[{"name":"Nemours Centers for Childhood Cancer Research and Cancer & Blood Disorders, Nemours Children\u2019s Health, Wilmington, DE 19803, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1001\/jama.2010.1862","article-title":"Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia","volume":"304","author":"Gentles","year":"2010","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.stem.2014.11.010","article-title":"Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy","volume":"15","author":"Bruedigam","year":"2014","journal-title":"Cell Stem Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nm.4439","article-title":"The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions","volume":"24","author":"Bolouri","year":"2018","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1073\/pnas.0807057106","article-title":"Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia","volume":"106","author":"Calado","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1038\/leu.2013.57","article-title":"Telomere length and telomerase complex mutations in pediatric acute myeloid leukemia","volume":"27","author":"Aalbers","year":"2013","journal-title":"Leukemia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1002\/cncr.11313","article-title":"Telomerase activity is prognostic in pediatric patients with acute myeloid leukemia: Comparison with adult acute myeloid leukemia","volume":"97","author":"Verstovsek","year":"2003","journal-title":"Cancer"},{"key":"ref_7","first-page":"3931","article-title":"A novel telomerase template antagonist (GRN163) as a potential anticancer agent","volume":"63","author":"Asai","year":"2003","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5262","DOI":"10.1038\/sj.onc.1208760","article-title":"Lipid modification of GRN163, an N3\u2019\u2192P5\u2019 thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition","volume":"24","author":"Herbert","year":"2005","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1056\/NEJMoa1503479","article-title":"Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia","volume":"373","author":"Baerlocher","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1200\/JCO.20.02864","article-title":"Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis","volume":"39","author":"Mascarenhas","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1200\/JCO.20.01895","article-title":"Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients with Lower-Risk Myelodysplastic Syndromes in a Phase II Study","volume":"39","author":"Steensma","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1056\/NEJMoa1310523","article-title":"A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis","volume":"373","author":"Tefferi","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_13","first-page":"2860","article-title":"Telomerase Inhibition Impairs Self-Renewal of \u00df-Catenin Activated Myeloproliferative Neoplasm Progenitors","volume":"130","author":"Ma","year":"2017","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1182\/bloodadvances.2018022012","article-title":"Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells","volume":"2","author":"Wang","year":"2018","journal-title":"Blood Adv."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Karow, A., Haubitz, M., Oppliger Leibundgut, E., Helsen, I., Preising, N., Steiner, D., Dantonello, T.M., Ammann, R.A., Roessler, J., and Kartal-Kaess, M. (2021). Targeting Telomere Biology in Acute Lymphoblastic Leukemia. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136653"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1038\/leu.2017.78","article-title":"Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis","volume":"31","author":"Mosoyan","year":"2017","journal-title":"Leukemia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3724","DOI":"10.1182\/bloodadvances.2019000167","article-title":"Imetelstat inhibits growth of megakaryocyte colony-forming units from patients with essential thrombocythemia","volume":"3","author":"Baerlocher","year":"2019","journal-title":"Blood Adv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"162","DOI":"10.3389\/fonc.2016.00162","article-title":"Generation of Pediatric Leukemia Xenograft Models in NSG-B2m Mice: Comparison with NOD\/SCID Mice","volume":"6","author":"Gopalakrishnapillai","year":"2016","journal-title":"Front. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e6","DOI":"10.5808\/GI.2020.18.1.e6","article-title":"Strong concordance between RNA structural and single nucleotide variants identified via next generation sequencing techniques in primary pediatric leukemia and patient-derived xenograft samples","volume":"18","author":"Barwe","year":"2020","journal-title":"Genom. Inf."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gopalakrishnapillai, A., Correnti, C.E., Pilat, K., Lin, I., Chan, M.K., Bandaranayake, A.D., Mehlin, C., Kisielewski, A., Hamill, D., and Kaeding, A.J. (2021). Immunotherapeutic Targeting of Mesothelin Positive Pediatric AML Using Bispecific T Cell Engaging Antibodies. Cancers, 13.","DOI":"10.3390\/cancers13235964"},{"key":"ref_21","first-page":"4403","article-title":"Human acute myeloid leukemia CD34+\/CD38- progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities","volume":"60","author":"Costello","year":"2000","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"659253","DOI":"10.3389\/fonc.2021.659253","article-title":"Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia","volume":"11","author":"Denkers","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s12185-017-2221-5","article-title":"Leukemic stem cells: Identification and clinical application","volume":"105","author":"Hanekamp","year":"2017","journal-title":"Int. J. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/bjh.14244","article-title":"Epigenetic landscape of the TERT promoter: A potential biomarker for high risk AML\/MDS","volume":"175","author":"Zhao","year":"2016","journal-title":"Br. J. Haematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.18632\/oncotarget.2917","article-title":"The DNA methylation inhibitor induces telomere dysfunction and apoptosis of leukemia cells that is attenuated by telomerase over-expression","volume":"6","author":"Zhang","year":"2015","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1158\/1538-7445.AM2016-2731","article-title":"Abstract 2731: Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines","volume":"76","author":"Rusbuldt","year":"2016","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.leukres.2017.05.004","article-title":"Epigenetic drug combination induces remission in mouse xenograft models of pediatric acute myeloid leukemia","volume":"58","author":"Gopalakrishnapillai","year":"2017","journal-title":"Leuk Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/leu.2012.312","article-title":"Azacitidine fails to eradicate leukemic stem\/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia","volume":"27","author":"Craddock","year":"2013","journal-title":"Leukemia"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/7\/1923\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:46:28Z","timestamp":1760136388000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/7\/1923"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,30]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["jcm11071923"],"URL":"https:\/\/doi.org\/10.3390\/jcm11071923","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,30]]}}}