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However, many ALL patients eventually develop relapses, the treatment of which remains a major challenge due to their chemoresistance phenotype. As a step towards this end, we here uncovered that relapsed ALL specimens exhibit a significantly lower expression of <jats:italic>STAT6<\/jats:italic> but not of other <jats:italic>STATs<\/jats:italic>, when compared with their paired diagnosis specimens. Furthermore, STAT6 plays a distinctive role in chemosensitization of ALL cells to cytarabine (Ara-C), and T-box transcription factor 21 <jats:italic>(TBX21)<\/jats:italic> emerged as a plausible intrinsic biomarker of this Ara-C chemosensitization. We demonstrate that STAT6 undergoes SUMOylation on Lys-307 and sentrin\/SUMO-specific protease 3 (SENP3)-mediated deSUMOylation in ALL cells. Most importantly, Ara-C specifically induced SENP3 expression and SENP3 knockdown sensitized ALL cells to Ara-C, with an impact equivalent to STAT6 knockout. These findings support the feedback resistance conferred upon ALL cells by Ara-C-induced SENP3 expression. Our findings uncover a novel role for STAT6 in ALL resistance to Ara-C and suggest that its targeted deprivation or pharmacological inhibition specifically sensitizes ALL cells to Ara-C, offering a plausible modality to surmount Ara-C resistance in future ALL treatment.<\/jats:p>","DOI":"10.1038\/s41419-025-07981-7","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T15:06:05Z","timestamp":1756825565000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeted deprivation of STAT6 sensitizes acute lymphoblastic leukemia cells to cytarabine in vivo and in vitro: clinical implications"],"prefix":"10.1038","volume":"16","author":[{"given":"Shuzhang","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiange","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinjie","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxin","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houshun","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunshuang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyi","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6692-8221","authenticated-orcid":false,"given":"Yehuda G.","family":"Assaraf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2860-694X","authenticated-orcid":false,"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hegen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4254-8117","authenticated-orcid":false,"given":"Ning","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,2]]},"reference":[{"key":"7981_CR1","doi-asserted-by":"crossref","unstructured":"Jacoby E, Gokbuget N, Nagler A. 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They were evaluated and approved by the Institutional Review Board of Shanghai Children\u2019s Medical Center (SCMC, Permit No. SCMCIRB-K2022098-1). All the patients have signed informed consent. Animal studies in this study followed the ARRIVE guidelines. They were evaluated and approved by the Institutional Animal Care and Use Committee of SCMC (Permit No. SCMC-LAWEC-2023-118).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"669"}}