{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:39:04Z","timestamp":1790933944519,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T00:00:00Z","timestamp":1672099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009093","name":"Fundaci\u00f3n Espa\u00f1ola de Hematolog\u00eda y Hemoterapia","doi-asserted-by":"publisher","award":["FEHH 2020"],"award-info":[{"award-number":["FEHH 2020"]}],"id":[{"id":"10.13039\/501100009093","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009093","name":"Fundaci\u00f3n Espa\u00f1ola de Hematolog\u00eda y Hemoterapia","doi-asserted-by":"publisher","award":["FEHH\u2010AbbVie 2017"],"award-info":[{"award-number":["FEHH\u2010AbbVie 2017"]}],"id":[{"id":"10.13039\/501100009093","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","award":["GLD17\/00232"],"award-info":[{"award-number":["GLD17\/00232"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FI20\/00053"],"award-info":[{"award-number":["FI20\/00053"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI13\/02099"],"award-info":[{"award-number":["PI13\/02099"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI19\/00374"],"award-info":[{"award-number":["PI19\/00374"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Studies prior to next\u2010generation sequencing (NGS) showed that the frequent indolent course of chronic lymphocytic leukaemia (CLL) is related to most cells remaining quiescent in the G<jats:sub>0<\/jats:sub>\u2013G<jats:sub>1<\/jats:sub> cell cycle phase, due to the expression of dysregulated cyclin genes. Of note, the activating nature of the <jats:italic>NOTCH1<\/jats:italic> mutation in T lymphoblastic leukaemia also drives the dysregulation of cell cycle genes. Our goal was to comprehensively revisit the cell cycle in <jats:italic>NOTCH1<\/jats:italic>\u2010mutated CLL (<jats:italic>NOTCH1<\/jats:italic><jats:sup>MUT<\/jats:sup><jats:italic>)<\/jats:italic> to test for potential therapeutic targets. Among 378 NGS\u2010annotated CLL cases, <jats:italic>NOTCH1<\/jats:italic><jats:sup>MUT<\/jats:sup> cells displayed a unique transcriptome profile of G<jats:sub>0<\/jats:sub>\u2013G<jats:sub>1<\/jats:sub> cell cycle components, with an overexpression of early\u2010phase effectors, reaching a 38\u2010, 27\u2010 and ninefold change increase for the complex elements <jats:italic>CCND3<\/jats:italic>, <jats:italic>CDK4<\/jats:italic> and <jats:italic>CDK6<\/jats:italic>, respectively. This <jats:italic>NOTCH1<\/jats:italic><jats:sup>MUT<\/jats:sup> cells\u2019 profile was related to more cells traversing through the cell cycle. <jats:italic>In\u2010vitro<\/jats:italic> targeted inhibition of NOTCH1 gamma\u2010secretase and CDK4\/6 reversed the distribution of cells through the cycle phases and enhanced the killing of <jats:italic>NOTCH1<\/jats:italic><jats:sup>MUT<\/jats:sup> CLL cells, suggesting new therapeutic approaches.<\/jats:p>","DOI":"10.1111\/bjh.18609","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T08:27:30Z","timestamp":1672129650000},"page":"470-479","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp><i>NOTCH1<\/i><\/scp> mutation in chronic lymphocytic leukaemia is associated with an enhanced cell cycle <scp>G1<\/scp>\/S transition and specific cyclin overexpression: Preclinical ground for targeted inhibition"],"prefix":"10.1111","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9740-0323","authenticated-orcid":false,"given":"Salvador","family":"Carrillo\u2010Tornel","sequence":"first","affiliation":[{"name":"Hematology and Medical Oncology Department Hospital Universitario Morales Meseguer, CRH\u2010IMIB, Universidad de Murcia  Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu Hua","family":"Chen\u2010Liang","sequence":"additional","affiliation":[{"name":"Hematology and Medical Oncology Department Hospital Universitario Morales Meseguer, CRH\u2010IMIB, Universidad de Murcia  Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Zurdo","sequence":"additional","affiliation":[{"name":"Hematology and Medical Oncology Department Hospital Universitario Morales Meseguer, CRH\u2010IMIB, Universidad de Murcia  Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9627-4978","authenticated-orcid":false,"given":"Anna","family":"Puiggros","sequence":"additional","affiliation":[{"name":"Molecular Cytogenetics Laboratory. Pathology Service Hospital del Mar  Barcelona Spain"},{"name":"Translational Research Group on Hematological Neoplasms Hospital del Mar Research Institute (IMIM)  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"G\u00f3mez\u2010Llon\u00edn","sequence":"additional","affiliation":[{"name":"Molecular Cytogenetics Laboratory. Pathology Service Hospital del Mar  Barcelona Spain"},{"name":"Translational Research Group on Hematological Neoplasms Hospital del Mar Research Institute (IMIM)  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Dolores","family":"Garc\u00eda\u2010Malo","sequence":"additional","affiliation":[{"name":"Hematology and Medical Oncology Department Hospital Universitario Morales Meseguer, CRH\u2010IMIB, Universidad de Murcia  Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto Jos\u00e9","family":"Cuenca\u2010Zamora","sequence":"additional","affiliation":[{"name":"Hematology and Medical Oncology Department Hospital Universitario Morales Meseguer, CRH\u2010IMIB, Universidad de Murcia  Murcia Spain"},{"name":"CB15\/00055\u2010CIBERER  Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco Jos\u00e9","family":"Ortu\u00f1o","sequence":"additional","affiliation":[{"name":"Hematology and Medical Oncology Department Hospital Universitario Morales Meseguer, CRH\u2010IMIB, Universidad de Murcia  Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3235-3690","authenticated-orcid":false,"given":"Ana Mar\u00eda Hurtado","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Hematology and Medical Oncology Department Hospital Universitario Morales Meseguer, CRH\u2010IMIB, Universidad de Murcia  Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4294-8145","authenticated-orcid":false,"given":"Blanca","family":"Espinet","sequence":"additional","affiliation":[{"name":"Molecular Cytogenetics Laboratory. Pathology Service Hospital del Mar  Barcelona Spain"},{"name":"Translational Research Group on Hematological Neoplasms Hospital del Mar Research Institute (IMIM)  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2079-6638","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Jerez","sequence":"additional","affiliation":[{"name":"Hematology and Medical Oncology Department Hospital Universitario Morales Meseguer, CRH\u2010IMIB, Universidad de Murcia  Murcia Spain"},{"name":"CB15\/00055\u2010CIBERER  Murcia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0239-8"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2006.040956"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.10.2870.bloodjournal85102870"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.12.4694"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402389"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10113"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1702564114"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0571-0"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110921"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.353"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-06-093906"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2015.65"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.143"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.11.006"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11003"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.298"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.21972"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.175"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V86.3.1090.1090"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.09.016"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.09.015"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-0098"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1400029"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.24928"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27863"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0609.2002.01515.x"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01475-7"}],"container-title":["British Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.18609","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bjh.18609","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.18609","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T02:55:36Z","timestamp":1692586536000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bjh.18609"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,27]]},"references-count":27,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,5]]}},"alternative-id":["10.1111\/bjh.18609"],"URL":"https:\/\/doi.org\/10.1111\/bjh.18609","archive":["Portico"],"relation":{},"ISSN":["0007-1048","1365-2141"],"issn-type":[{"value":"0007-1048","type":"print"},{"value":"1365-2141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,27]]},"assertion":[{"value":"2022-11-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}