{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:20:22Z","timestamp":1791274822893,"version":"4.1.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"4","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,1,27]]},"abstract":"<jats:p>\n                    Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone marrow samples from 133 consecutive patients with acute myeloid leukemia and 198 controls for variations in\n                    <jats:italic>TERT<\/jats:italic>\n                    and\n                    <jats:italic>TERC<\/jats:italic>\n                    genes. An additional 89 patients from a second cohort, selected based on cytogenetic status, and 528 controls were further examined for mutations. A third cohort of 372 patients and 384 controls were specifically tested for one\n                    <jats:italic>TERT<\/jats:italic>\n                    gene variant. In the first cohort, 11 patients carried missense\n                    <jats:italic>TERT<\/jats:italic>\n                    gene variants that were not present in controls (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001); in the second cohort,\n                    <jats:italic>TERT<\/jats:italic>\n                    mutations were associated with trisomy 8 and inversion 16. Mutation germ-line origin was demonstrated in 5 patients from whom other tissues were available. Analysis of all 3 cohorts (\n                    <jats:italic>n<\/jats:italic>\n                    = 594) for the most common gene variant (A1062T) indicated a prevalence 3 times higher in patients than in controls (\n                    <jats:italic>n<\/jats:italic>\n                    = 1,110;\n                    <jats:italic>P<\/jats:italic>\n                    = 0.0009). Introduction of\n                    <jats:italic>TERT<\/jats:italic>\n                    mutants into telomerase-deficient cells resulted in loss of enzymatic activity by haploinsufficiency. Inherited mutations in\n                    <jats:italic>TERT<\/jats:italic>\n                    that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0807057106","type":"journal-article","created":{"date-parts":[[2009,1,15]],"date-time":"2009-01-15T21:44:30Z","timestamp":1232055870000},"page":"1187-1192","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":161,"title":["Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia"],"prefix":"10.1073","volume":"106","author":[{"given":"Rodrigo T.","family":"Calado","sequence":"first","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A.","family":"Regal","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Hills","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada V5Z 4E6; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Yewdell","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro F.","family":"Dalmazzo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Center of Cell-Based Therapy, University of S\u00e3o Paulo at Ribeir\u00e3o Preto Medical School, SP 14048-900, Ribeir\u00e3o Preto, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco A.","family":"Zago","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Center of Cell-Based Therapy, University of S\u00e3o Paulo at Ribeir\u00e3o Preto Medical School, SP 14048-900, Ribeir\u00e3o Preto, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Lansdorp","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada V5Z 4E6; and"},{"name":"Department of Medicine, University of British Columbia Cancer Center, Vancouver, BC, Canada V6T 1Z4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Hogge","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada V5Z 4E6; and"},{"name":"Department of Medicine, University of British Columbia Cancer Center, Vancouver, BC, Canada V6T 1Z4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Chanock","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elihu H.","family":"Estey","sequence":"additional","affiliation":[{"name":"Leukemia Department, University of Texas MD Anderson Cancer Center, Houston, TX 77030;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto P.","family":"Falc\u00e3o","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Center of Cell-Based Therapy, University of S\u00e3o Paulo at Ribeir\u00e3o Preto Medical School, SP 14048-900, Ribeir\u00e3o Preto, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal S.","family":"Young","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,1,27]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00492-5"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/newbio239197a0"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-09-084913"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-08-019729"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0598-32"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2004.12.008"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/35096585"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2007.10.004"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa042980"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-09-3659"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)14797-6"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa066157"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701009104"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2000.02109.x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-03-010777"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-07-035089"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69780-8"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergencyto.2006.05.008"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-10-120907"},{"key":"e_1_3_3_20_2","article-title":"TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program","author":"Choi J","year":"2008","unstructured":"J Choi, et al., TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. PLoS Genet, 2008).","journal-title":"PLoS Genet"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1346"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.2005.70.032"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/35020592"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-06-030312"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80580-2"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003318"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1409"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djg011"},{"key":"e_1_3_3_29_2","first-page":"799","article-title":"Telomerase activity in human acute myelogenous leukemia: inhibition of telomerase activity by differentiation-inducing agents","volume":"2","author":"Zhang W","year":"1996","unstructured":"W Zhang, et al., Telomerase activity in human acute myelogenous leukemia: inhibition of telomerase activity by differentiation-inducing agents. Clin Cancer Res 2, 799\u2013803 (1996).","journal-title":"Clin Cancer Res"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.06.00087005"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2006.12.006"},{"key":"e_1_3_3_32_2","first-page":"351","volume-title":"World Health Organization Classification of Tumours","author":"Jaffe ES","year":"2001","unstructured":", eds ES Jaffe, NL Harris, H Stein, JW Wardiman (IARC, Lyon, France), Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumours, pp. 351 (2001)."},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-103-4-620"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-103-3-460"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1991.tb04444.x"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.5.725"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0807057106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T18:02:46Z","timestamp":1649786566000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0807057106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,1,27]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009,1,27]]}},"alternative-id":["10.1073\/pnas.0807057106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0807057106","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1159201.619524","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,1,27]]},"assertion":[{"value":"2008-07-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-01-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}