{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:32:31Z","timestamp":1788838351700,"version":"build-2803163510"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"9","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFA0801000"],"award-info":[{"award-number":["2018YFA0801000"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MOST | National Natural Science Foundation of China (NSFC)\/Research Grants Council (RGC) Joint Research Scheme","award":["32161160326"],"award-info":[{"award-number":["32161160326"]}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770167"],"award-info":[{"award-number":["81770167"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070163"],"award-info":[{"award-number":["82070163"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,3,4]]},"abstract":"<jats:p>\n                    Approximately 30% of patients with myelodysplastic syndrome (MDS) progress to secondary acute myeloid leukemia (sAML) via accumulating gene mutations. Genomic analyses reveal a complex interplay among mutant genes, with co-occurring and mutually exclusive patterns. Hyperactivation of c-MYB and deficiency of PU.1 have been linked to myeloid disorders. We report a case of AML with concurrent\n                    <jats:italic>PU.1<\/jats:italic>\n                    and\n                    <jats:italic>c-MYB<\/jats:italic>\n                    mutations, exhibiting early onset, high blast count, chemo-resistance, indicating high-risk features, along with elevated Pelger\u2013Hu\u00ebt anomaly (PHA). However, the synergistic mechanism of\n                    <jats:italic>c-MYB<\/jats:italic>\n                    and\n                    <jats:italic>PU.1<\/jats:italic>\n                    in sAML remains unclear. Using c-Myb-hyperactivation and Pu.1-deficient double-strain (\n                    <jats:italic>\n                      c-myb\n                      <jats:sup>hyper<\/jats:sup>\n                      ;pu.1\n                      <jats:sup>G242D\/G242D<\/jats:sup>\n                    <\/jats:italic>\n                    ) zebrafish, we investigated MDS\/sAML progression. Surprisingly, the double mutant exhibited a distinct type of neutrophil resembling clinical PHA cells and demonstrated a higher rate of MDS\/sAML transformation. Further expression analysis revealed reduced\n                    <jats:italic>lmnb1<\/jats:italic>\n                    expression in double-mutant zebrafish. Knockdown of\n                    <jats:italic>lmnb1<\/jats:italic>\n                    resulted in PHA and increased blast cells, while overexpression of\n                    <jats:italic>lmnb1<\/jats:italic>\n                    in\n                    <jats:italic>\n                      c-myb\n                      <jats:sup>hyper<\/jats:sup>\n                      ;pu.1\n                      <jats:sup>G242D\/G242D<\/jats:sup>\n                    <\/jats:italic>\n                    reduced PHA cell level. This suggests that c-Myb hyperactivation and Pu.1 deficiency synergistically reduce\n                    <jats:italic>lmnb1<\/jats:italic>\n                    expression, inducing the development of PHA-like neutrophils and promoting MDS\/sAML progression in zebrafish. Moreover, coadministration of cell cycle inhibitor cytarabine (Ara-C) and the differential inducer all-trans retinoic acid (ATRA) could effectively relieve the neutrophil expansion and PHA symptoms in\n                    <jats:italic>\n                      c-myb\n                      <jats:sup>hyper<\/jats:sup>\n                      ;pu.1\n                      <jats:sup>G242D\/G242D<\/jats:sup>\n                    <\/jats:italic>\n                    zebrafish. Our findings revealed that c-Myb hyperactivation and Pu.1 deficiency played a synergistic role in sAML development and suggests a phenotypic association between the emergence of PH-like cells and the transformation to sAML. Furthermore,\n                    <jats:italic>\n                      c-myb\n                      <jats:sup>hyper<\/jats:sup>\n                      ;pu.1\n                      <jats:sup>G242D\/G242D<\/jats:sup>\n                    <\/jats:italic>\n                    zebrafish might serve as a suitable sAML model for drug screening.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2416121122","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T15:34:48Z","timestamp":1740756888000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["The synergistic effect of c-Myb hyperactivation and Pu.1 deficiency induces Pelger\u2013Hu\u00ebt anomaly and promotes sAML"],"prefix":"10.1073","volume":"122","author":[{"given":"Song\u2019en","family":"Xu","sequence":"first","affiliation":[{"name":"Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4399-9083","authenticated-orcid":false,"given":"Jiaxin","family":"Hong","sequence":"additional","affiliation":[{"name":"Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meimei","family":"Dongye","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiehao","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongtao","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Hematology, Nanfang Hospital, Southern Medical University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4286-4002","authenticated-orcid":false,"given":"Zhibin","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6840-1359","authenticated-orcid":false,"given":"Jin","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9402-3523","authenticated-orcid":false,"given":"Yiyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anskar Yu-Hung","family":"Leung","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong","place":["Hong Kong, Special Administrative Region of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Marine Pharmacy, School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University","place":["Guangzhou, China"]},{"name":"Guangdong Key Laboratory of 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