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Here, we use high resolution imaging to demonstrate that NPM1 is crucial for maintaining normal nucleoli architecture and specifically the integrity of the enigmatic nucleoli rim, the least understood nucleolar compartment. We demonstrate that cell lines and primary cells with NPM1 mutations from individuals with AML have aberrant nucleoli architecture; intriguingly this abnormal nucleolar phenotype is reversible. Using a surrogate for rRNA synthesis, we show that the aberrant phenotype is associated with differences in nucleolar function; specifically, activity of RNA polymerase I is increased in NPM1 mutated cells. Perinucleolar chromatin organisation is also markedly different in NPM1 mutant cells. Finally, we report the novel finding that NPM1 mutated protein forms distinct aggregates and characterise these for the first time. This work reveals how nucleolar organisation contributes to the molecular mechanisms underpinning NPM1-driven AML, revealing novel therapeutic vulnerabilities.<\/jats:p>","DOI":"10.1242\/jcs.263553","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T08:32:40Z","timestamp":1745310760000},"source":"Crossref","is-referenced-by-count":1,"title":["Abnormal nucleoli architecture and aggregate formation in nucleophosmin mutated acute myeloid leukaemia"],"prefix":"10.1242","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0719-2469","authenticated-orcid":false,"given":"Martin","family":"Grundy","sequence":"first","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham 1 Translational Medical Sciences , , Nottingham NG7 2RD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6175-7697","authenticated-orcid":false,"given":"Kellie","family":"Lucken","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham 1 Translational Medical Sciences , , Nottingham NG7 2RD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomeng","family":"Xing","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham 1 Translational Medical Sciences , , Nottingham NG7 2RD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva L.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham 1 Translational Medical Sciences , , Nottingham NG7 2RD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Worker","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham 1 Translational Medical Sciences , , Nottingham NG7 2RD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2749-0758","authenticated-orcid":false,"given":"Ahmed","family":"Bayyoomi","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham 1 Translational Medical Sciences , , Nottingham NG7 2RD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison J.","family":"Beckett","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool 2 Molecular Physiology and Cell Signalling , , Liverpool L69 7BE ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian A.","family":"Prior","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool 2 Molecular Physiology and Cell Signalling , , Liverpool L69 7BE ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6216-2863","authenticated-orcid":false,"given":"Daniel G.","family":"Booth","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham 1 Translational Medical Sciences , , Nottingham NG7 2RD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2280-4045","authenticated-orcid":false,"given":"Claire H.","family":"Seedhouse","sequence":"additional","affiliation":[{"name":"Biodiscovery Institute, University of Nottingham 1 Translational Medical Sciences , , Nottingham NG7 2RD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"2025052104395429300_JCS263553C1","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1111\/bjh.15823","article-title":"DNA damage corrects the aberrant cytoplasmic localisation of nucleophosmin in NPM1 mutated acute myeloid leukaemia","volume":"186","author":"Bailey","year":"2019","journal-title":"Br. 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