{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:14:39Z","timestamp":1791947679149,"version":"4.3.4"},"reference-count":15,"publisher":"American Association for the Advancement of Science (AAAS)","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170143"],"award-info":[{"award-number":["82170143"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370191"],"award-info":[{"award-number":["82370191"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82200160"],"award-info":[{"award-number":["82200160"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012165","name":"Key Technologies Research and Development Program","doi-asserted-by":"publisher","award":["2022YFE0119700"],"award-info":[{"award-number":["2022YFE0119700"]}],"id":[{"id":"10.13039\/501100012165","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005891","name":"State Administration of Traditional Chinese Medicine of the People's Republic of China","doi-asserted-by":"publisher","award":["zyyzdxk-2023303"],"award-info":[{"award-number":["zyyzdxk-2023303"]}],"id":[{"id":"10.13039\/501100005891","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["spj.science.org"],"crossmark-restriction":true},"short-container-title":["Research"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n            Arsenic trioxide (ATO) is able to selectively target and degrade the disease-causing PML::RAR\u03b1 (P\/R) oncoprotein in acute promyelocytic leukemia (APL) for curing the disease. However, some relapsed patients develop resistance to ATO due to mutations in the promyelocytic leukemia (PML) part of the\n            <jats:italic toggle=\"yes\">PML::RAR\u03b1<\/jats:italic>\n            fusion gene. A relapsed APL patient had shown resistance to ATO and chemotherapy and was identified to harbor a point mutation (A216V) in the unrearranged\n            <jats:italic toggle=\"yes\">PML<\/jats:italic>\n            allele rather than the\n            <jats:italic toggle=\"yes\">PML::RAR\u03b1<\/jats:italic>\n            fusion gene. Here, we report that mutations in the unrearranged\n            <jats:italic toggle=\"yes\">PML<\/jats:italic>\n            allele impede the ATO-induced destabilization and degradation of the wild-type P\/R oncoprotein. Deletion of the coiled-coil domain in a PML mutant completely reversed wild-type P\/R protein resistance to ATO by abolishing the interaction between PML and P\/R proteins. Collectively, our findings reveal that a point mutation in the unrearranged\n            <jats:italic toggle=\"yes\">PML<\/jats:italic>\n            allele can confer ATO resistance through a protein\u2013protein interaction. Therefore, the unrearranged\n            <jats:italic toggle=\"yes\">PML<\/jats:italic>\n            allele should also be screened for drug-resistant mutations in relapsed APL patients.\n          <\/jats:p>","DOI":"10.34133\/research.0696","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T01:08:19Z","timestamp":1746061699000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":9,"title":["Mutation in the Unrearranged\n            <i>PML<\/i>\n            Allele Confers Resistance to Arsenic Trioxide in Acute Promyelocytic Leukemia"],"prefix":"10.34133","volume":"8","author":[{"given":"Pei-Han","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Hematology of First Affiliated Hospital, \rZhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Department of Public Health, \rZhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Department of Pharmacology, \rZhejiang University, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Ying","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Hematology of First Affiliated Hospital, \rZhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Department of Public Health, \rZhejiang University School of Medicine, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Yuan","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Hematology of First Affiliated Hospital, \rZhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Department of Public Health, \rZhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Department of Pharmacology, \rZhejiang University, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0799-2340","authenticated-orcid":true,"given":"Hua","family":"Naranmandura","sequence":"additional","affiliation":[{"name":"Department of Hematology of First Affiliated Hospital, \rZhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Department of Public Health, \rZhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Department of Pharmacology, \rZhejiang University, Hangzhou 310058, China."},{"name":"Cancer Center, \rZhejiang University, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hematology of First Affiliated Hospital, \rZhejiang University School of Medicine, Hangzhou 310058, China."},{"name":"Department of Public Health, \rZhejiang University School of Medicine, Hangzhou 310058, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"issue":"6293","key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/347558a0","article-title":"The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor \u03b1 gene to a novel transcribed locus","volume":"347","author":"Th\u00e9 H","year":"1990","unstructured":"de Th\u00e9 H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor \u03b1 gene to a novel transcribed locus. Nature. 1990;347(6293):558\u2013561.","journal-title":"Nature"},{"issue":"6","key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1073\/pnas.94.6.2551","article-title":"A PMLRAR\u03b1 transgene initiates murine acute promyelocytic leukemia","volume":"94","author":"Brown D","year":"1997","unstructured":"Brown D, Kogan S, Lagasse E, Weissman I, Alcalay M, Pelicci PG, Atwater S, Bishop JM. A PMLRAR\u03b1 transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci USA. 1997;94(6):2551\u20132556.","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)80044-F"},{"issue":"15","key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1182\/blood-2019-01-894980","article-title":"Management of acute promyelocytic leukemia: Updated recommendations from an expert panel of the European LeukemiaNet","volume":"133","author":"Sanz MA","year":"2019","unstructured":"Sanz MA, Fenaux P, Tallman MS, Estey EH, L\u00f6wenberg B, Naoe T, Lengfelder E, D\u00f6hner H, Burnett AK, Chen SJ, et al. Management of acute promyelocytic leukemia: Updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019;133(15):1630\u20131643.","journal-title":"Blood"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1183424"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-0453"},{"issue":"13","key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"4298","DOI":"10.1182\/blood-2002-02-0632","article-title":"All-trans retinoic acid in acute promyelocytic leukemia: Long-term outcome and prognostic factor analysis from the North American Intergroup protocol","volume":"100","author":"Tallman MS","year":"2002","unstructured":"Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, Ogden A, Weinstein H, Shepherd L, Willman C, et al. All-trans retinoic acid in acute promyelocytic leukemia: Long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002;100(13):4298\u20134302.","journal-title":"Blood"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1316382"},{"issue":"6","key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1038\/s41375-018-0298-3","article-title":"Early and sensitive detection of PML-A216V mutation by droplet digital PCR in ATO-resistant acute promyelocytic leukemia","volume":"33","author":"Alfonso V","year":"2019","unstructured":"Alfonso V, Iaccarino L, Ottone T, Cicconi L, Lavorgna S, Divona M, Cairoli R, Cristiano A, Ciardi C, Travaglini S, et al. Early and sensitive detection of PML-A216V mutation by droplet digital PCR in ATO-resistant acute promyelocytic leukemia. Leukemia. 2019;33(6):1527\u20131530.","journal-title":"Leukemia"},{"issue":"6","key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/bjh.13910","article-title":"Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia","volume":"172","author":"Iaccarino L","year":"2016","unstructured":"Iaccarino L, Ottone T, Divona M, Cicconi L, Cairoli R, Voso MT, Lo-Coco F. Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia. Br J Haematol. 2016;172(6):909\u2013913.","journal-title":"Br J Haematol"},{"issue":"5","key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/ncb1717","article-title":"Arsenic degrades PML or PML\u2013RAR\u03b1 through a SUMO-triggered RNF4\/ubiquitin-mediated pathway","volume":"10","author":"Lallemand-Breitenbach V","year":"2008","unstructured":"Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de Th\u00e9 H. Arsenic degrades PML or PML\u2013RAR\u03b1 through a SUMO-triggered RNF4\/ubiquitin-mediated pathway. Nat Cell Biol. 2008;10(5):547\u2013555.","journal-title":"Nat Cell Biol"},{"issue":"4","key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1073\/pnas.93.4.1601","article-title":"In vivo and in\u00a0vitro characterization of the B1 and B2 zinc-binding domains from the acute promyelocytic leukemia protooncoprotein PML","volume":"93","author":"Borden KL","year":"1996","unstructured":"Borden KL, Lally JM, Martin SR, O\u2019Reilly NJ, Solomon E, Freemont PS. In vivo and in\u00a0vitro characterization of the B1 and B2 zinc-binding domains from the acute promyelocytic leukemia protooncoprotein PML. Proc Natl Acad Sci USA. 1996;93(4):1601\u20131606.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1038\/s41467-018-03498-0","article-title":"RING tetramerization is required for nuclear body biogenesis and PML sumoylation","volume":"9","author":"Wang P","year":"2018","unstructured":"Wang P, Benhenda S, Wu H, Lallemand-Breitenbach V, Zhen T, Jollivet F, Peres L, Li Y, Chen SJ, Chen Z, et al. RING tetramerization is required for nuclear body biogenesis and PML sumoylation. Nat Commun. 2018;9(1):1277.","journal-title":"Nat Commun"},{"issue":"1","key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"3789","DOI":"10.1038\/s41467-019-11746-0","article-title":"B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis","volume":"10","author":"Li Y","year":"2019","unstructured":"Li Y, Ma X, Chen Z, Wu H, Wang P, Wu W, Cheng N, Zeng L, Zhang H, Cai X, et al. B1 oligomerization regulates PML nuclear body biogenesis and leukemogenesis. Nat Commun. 2019;10(1):3789.","journal-title":"Nat Commun"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.18"}],"container-title":["Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/spj.science.org\/doi\/pdf\/10.34133\/research.0696","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T13:04:25Z","timestamp":1746536665000},"score":1,"resource":{"primary":{"URL":"https:\/\/spj.science.org\/doi\/10.34133\/research.0696"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":15,"alternative-id":["10.34133\/research.0696"],"URL":"https:\/\/doi.org\/10.34133\/research.0696","relation":{},"ISSN":["2639-5274"],"issn-type":[{"value":"2639-5274","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2025-03-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-14","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"0696"}}