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The biologically relevant functions of HDAC10 in leukemia cells are enigmatic. We demonstrate that human cultured and primary acute B cell\/T cell leukemia and lymphoma cells require the catalytic activity of HDAC10 for their survival. In such cells, HDAC10 controls a MYC-dependent transcriptional induction of the DNA polymerase subunit POLD1. Consequently, pharmacological inhibition of HDAC10 causes DNA breaks and an accumulation of poly-ADP-ribose chains. These processes culminate in caspase-dependent apoptosis. PZ48 does not damage resting and proliferating human normal blood cells. The in vivo activity of PZ48 against ALL cells is verified in a\n                    <jats:italic>Danio rerio<\/jats:italic>\n                    model. These data reveal a nuclear function for HDAC10. HDAC10 controls the MYC-POLD1 axis to maintain the processivity of DNA replication and genome integrity. This mechanistically defined \u201cHDAC10ness\u201d may be exploited as treatment option for lymphoid malignancies.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02612-8","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T02:25:05Z","timestamp":1745893505000},"page":"1756-1768","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8672-0708","authenticated-orcid":false,"given":"Andreas O.","family":"Mieland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2835-4308","authenticated-orcid":false,"given":"Giuseppe","family":"Petrosino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Dejung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Xuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amitkumar","family":"Fulzele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fereshteh","family":"Mahmoudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Wey","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8850-6409","authenticated-orcid":false,"given":"Al-Hassan M.","family":"Mustafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2501-8149","authenticated-orcid":false,"given":"Yanira","family":"Zeyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3343-4203","authenticated-orcid":false,"given":"Christoph","family":"Hieber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4662-0542","authenticated-orcid":false,"given":"Matthias","family":"Bros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6351-4119","authenticated-orcid":false,"given":"Tina M.","family":"Schn\u00f6der","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2438-1955","authenticated-orcid":false,"given":"Florian H.","family":"Heidel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Najafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0827-2356","authenticated-orcid":false,"given":"Ina","family":"Oehme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3586-5050","authenticated-orcid":false,"given":"Ilse","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Schutkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Hilscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8387-3653","authenticated-orcid":false,"given":"Christian","family":"Kosan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7197-7279","authenticated-orcid":false,"given":"Falk","family":"Butter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6494-7744","authenticated-orcid":false,"given":"Sanil","family":"Bhatia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-9261","authenticated-orcid":false,"given":"Wolfgang","family":"Sippl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3973-045X","authenticated-orcid":false,"given":"Oliver H.","family":"Kr\u00e4mer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"2612_CR1","doi-asserted-by":"crossref","unstructured":"San Jose-Eneriz E, Gimenez-Camino N, Agirre X, Prosper F. 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None of these patents cover substance classes that are discussed in this work. The BASF has not promoted, sponsored, or supported this study in any way and its products are not discussed in this publication. I.O. receives research grants from PreComb, BVD, and Day One Therapeutics.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. Mice experiments were performed in compliance with the regulatory guidelines of LANUV (Akt. 81-02.04.2017.A441) and were approved by the animal research institute (ZETT) at Heinrich Heine University D\u00fcsseldorf. Patient samples were collected with informed consent, in accordance with the Declaration of Helsinki, and the experiments were approved by the ethics committee of the medical faculty at Heinrich Heine University (Study Nr.: 2019-566). PBMCs were isolated from blood samples that were obtained from healthy anonymous donors at the Transfusion Centre of the University Medical Centre of the Johannes Gutenberg University Mainz after informed consent. Human HSPCs derived from healthy donors were obtained after informed consent and according to the Helsinki declaration. Scientific protocol, patient information, and patient approval forms were approved by the respective local ethics committees (Ethics Committee, University Medicine Greifswald BB_199-20; Hannover Medical School 11501_BO_K_2024). Institutional Review Board Statement Zebrafish husbandry (permit number 35-9185.64\/BH Hassel) and experiments (permit number 35-9185.81\/G-234\/20) were performed according to local animal welfare standards (Tierschutzgesetz \u00a711, Abs. 1, No. 1) and in accordance with European Union animal welfare guidelines (EU Directive 2010\/63\/EU). All applicable national and institutional guidelines for the care and use of zebrafish were followed.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}