{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:14:28Z","timestamp":1753892068988,"version":"3.41.2"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T00:00:00Z","timestamp":1749772800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Indroduction<\/jats:title><jats:p>Ara\u2010C (cytarabine) resistance remains a significant contributor to the poor clinical outcomes in adult acute myeloid leukemia (AML). However, predicting Ara\u2010C resistance and developing effective targeted therapies remain challenging.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we integrated transcriptional data from Ara\u2010C\u2010resistant cell lines in the GEO database and the TCGA\u2010LAML cohort to establish an Ara\u2010C resistancerelated gene risk score (ARRGRS). Kaplan\u2010Meier survival analysis revealed that AML patients with high ARRGRS had significantly worse prognosis compared to those with low ARRGRS in both cohorts. Additionally, ARRGRS effectively predicted chemotherapy response in AML patients across both cohorts. To further elucidate the mechanisms underlying Ara\u2010C resistance, we constructed Ara\u2010C\u2010resistant AML cell lines and validated our findings using qPCR, Western blotting, flow cytometry (FCM), and in vivo experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We discovered that high expression of S100A4 promotes Ara\u2010C resistance in AML. Mechanistically, we identified that the transcription factor NR6A1 directly binds to the S100A4 promoter, enhancing its transcriptional activity. Subsequently, S100A4 upregulates p53 expression, thereby promoting AML cell proliferation and resistance to Ara\u2010C.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In summary, our comprehensive investigation of the ARRGRS not only deepens the understanding of Ara\u2010C resistance mechanisms but also provides promising insights for targeting S100A4 to inhibit tumor growth and overcome chemotherapy resistance in AML.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1574759","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T05:48:54Z","timestamp":1749793734000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of an Ara-C resistance-related gene risk score and the role of S100A4 in AML via NR6A1-dependent activation and p53 regulation"],"prefix":"10.3389","volume":"16","author":[{"given":"Li","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aoshuang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingqing","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuying","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jishi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/s41375-019-0596-4","article-title":"Integrated nuclear proteomics and transcriptomics identifies S100A4 as a therapeutic target in acute myeloid leukemia","volume":"34","author":"Alanazi","year":"2020","journal-title":"Leukemia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.annonc.2022.11.004","article-title":"Moving toward individualized target-based therapies in acute myeloid leukemia","volume":"34","author":"Bazinet","year":"2023","journal-title":"Ann. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1001\/jamaoncol.2022.7605","article-title":"Allogeneic hematopoietic cell transplantation vs standard consolidation chemotherapy in patients with intermediate-risk acute myeloid leukemia: a randomized clinical trial","volume":"9","author":"Bornh\u00e4user","year":"2023","journal-title":"JAMA Oncol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1002\/ajh.26700","article-title":"Retrospective comparison of survival and responses to Fludarabine, Cytarabine, GCSF (FLAG) in combination with gemtuzumab ozogamicin (GO) or Idarubicin (IDA) in patients with newly diagnosed core binding factor (CBF) acute myelogenous leukemia: MD Anderson experience in 174 patients","volume":"97","author":"Borthakur","year":"2022","journal-title":"Am. J. Hematol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"6356","DOI":"10.3390\/ijms25126356","article-title":"Monocytic differentiation in acute myeloid leukemia cells: diagnostic criteria, biological heterogeneity, mitochondrial metabolism, resistance to and induction by targeted therapies","volume":"25","author":"Bruserud","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1038\/s41392-020-00361-x","article-title":"Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy","volume":"5","author":"Carter","year":"2020","journal-title":"Signal Transduct. Target Ther."},{"key":"B7","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/s41375-024-02136-7","article-title":"Inflammatory recruitment of healthy hematopoietic stem and progenitor cells in the acute myeloid leukemia niche","volume":"38","author":"Chen","year":"2024","journal-title":"Leukemia"},{"key":"B8","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and venetoclax in previously untreated acute myeloid leukemia","volume":"383","author":"DiNardo","year":"","journal-title":"N. Engl. J. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1182\/blood.2019003988","article-title":"Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML","volume":"135","author":"DiNardo","year":"","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1182\/blood.2019001239","article-title":"How I treat acute myeloid leukemia in the era of new drugs","volume":"135","author":"DiNardo","year":"2020","journal-title":"Blood"},{"key":"B11","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/j.tips.2024.03.005","article-title":"AML treatment: conventional chemotherapy and emerging novel agents","volume":"45","author":"Forsberg","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.1182\/blood.2021014472","article-title":"Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome","volume":"139","author":"Grob","year":"2022","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1158\/1078-0432.CCR-22-2837","article-title":"Human effectors of acute and chronic GVHD overexpress CD83 and predict mortality","volume":"29","author":"Holtan","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41408-024-01143-2","article-title":"Current status and research directions in acute myeloid leukemia","volume":"14","author":"Kantarjian","year":"","journal-title":"Blood Cancer J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41408-021-00425-3","article-title":"Acute myeloid leukemia: current progress and future directions","volume":"11","author":"Kantarjian","year":"2021","journal-title":"Blood Cancer J."},{"key":"B16","doi-asserted-by":"publisher","first-page":"46","DOI":"10.3322\/caac.21873","article-title":"Acute myeloid leukemia management and research in 2025","volume":"75","author":"Kantarjian","year":"","journal-title":"CA Cancer J. Clin."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2684","DOI":"10.1200\/JCO.2017.77.6112","article-title":"CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia","volume":"36","author":"Lancet","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e481","DOI":"10.1016\/S2352-3026(21)00134-4","article-title":"CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial","volume":"8","author":"Lancet","year":"2021","journal-title":"Lancet Haematol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"107638","DOI":"10.1016\/j.leukres.2024.107638","article-title":"Combination therapy involving azacitidine for acute myeloid leukemia patients ineligible for intensive chemotherapy","volume":"148","author":"Li","year":"2024","journal-title":"Leuk. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"901","DOI":"10.14218\/JCTH.2022.00191","article-title":"Establishment of a prognostic model for hepatocellular carcinoma based on bioinformatics and the role of NR6A1 in the progression of HCC","volume":"10","author":"Lin","year":"2022","journal-title":"J. Clin. Transl. Hepatol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41375-022-01755-2","article-title":"Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia","volume":"37","author":"Ling","year":"2023","journal-title":"Leukemia"},{"key":"B22","doi-asserted-by":"publisher","first-page":"7516","DOI":"10.1074\/jbc.RA118.004365","article-title":"S100A4 alters metabolism and promotes invasion of lung cancer cells by up-regulating mitochondrial complex I protein NDUFS2","volume":"294","author":"Liu","year":"2019","journal-title":"J. Biol. Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e002548","DOI":"10.1136\/jitc-2021-002548","article-title":"S100A4 enhances protumor macrophage polarization by control of PPAR-\u03b3-dependent induction of fatty acid oxidation","volume":"9","author":"Liu","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s40164-021-00220-7","article-title":"Exosomes from BM-MSCs promote acute myeloid leukemia cell proliferation, invasion and chemoresistance via upregulation of S100A4","volume":"10","author":"Lyu","year":"2021","journal-title":"Exp. Hematol. Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1182\/blood.2023019782","article-title":"Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML","volume":"142","author":"Man","year":"2023","journal-title":"Blood"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1182\/bloodadvances.2022008018","article-title":"EVI1 exerts distinct roles in AML via ERG and cyclin D1 promoting a chemoresistant and immune-suppressive environment","volume":"7","author":"Masamoto","year":"2023","journal-title":"Blood Adv."},{"key":"B27","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1046\/j.1365-2141.2001.02756.x","article-title":"Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia","volume":"113","author":"Matthews","year":"2001","journal-title":"Br. J. Haematol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1158\/2159-8290.CD-19-0125","article-title":"The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells","volume":"9","author":"Nechiporuk","year":"2019","journal-title":"Cancer Discov."},{"key":"B29","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1158\/2159-8290.CD-19-0710","article-title":"Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia","volume":"10","author":"Pei","year":"2020","journal-title":"Cancer Discov."},{"key":"B30","doi-asserted-by":"publisher","first-page":"5080","DOI":"10.3390\/ijms25105080","article-title":"Monocytic differentiation of human acute myeloid leukemia cells: a proteomic and phosphoproteomic comparison of FAB-M4\/M5 patients with and without nucleophosmin 1 mutations","volume":"25","author":"Selheim","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s13148-022-01242-6","article-title":"A validation study of potential prognostic DNA methylation biomarkers in patients with acute myeloid leukemia using a custom DNA methylation sequencing panel","volume":"14","author":"\u0160est\u00e1kov\u00e1","year":"2022","journal-title":"Clin. Epigenetics"},{"key":"B32","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression shrinkage and selection via the lasso","volume":"58","author":"Tibshirani","year":"1996","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e415","DOI":"10.1016\/S2352-3026(22)00106-5","article-title":"Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy as first-line treatment for adults with acute myeloid leukaemia: a multicentre, single-arm, phase 2 trial","volume":"9","author":"Wang","year":"2022","journal-title":"Lancet Haematol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1016\/j.bcp.2009.03.011","article-title":"Intracellular cytarabine triphosphate production correlates to deoxycytidine kinase\/cytosolic 5\u2019-nucleotidase II expression ratio in primary acute myeloid leukemia cells","volume":"77","author":"Yamauchi","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1016\/j.jfma.2022.11.003","article-title":"The clinical and biological characterization of acute myeloid leukemia patients with S100A4 overexpression","volume":"122","author":"Yao","year":"2023","journal-title":"J. Formos. Med. Assoc."},{"key":"B37","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s40364-024-00579-9","article-title":"p53 biology and reactivation for improved therapy in MDS and AML","volume":"12","author":"Zawacka","year":"2024","journal-title":"Biomark. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2141","DOI":"10.1113\/EP088399","article-title":"hsa_circ_001653 up-regulates NR6A1 expression and elicits gastric cancer progression by binding to microRNA-377","volume":"105","author":"Zhou","year":"2020","journal-title":"Exp. Physiol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1574759\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T05:48:55Z","timestamp":1749793735000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1574759\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,13]]},"references-count":38,"alternative-id":["10.3389\/fphar.2025.1574759"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1574759","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2025,6,13]]},"article-number":"1574759"}}