{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T20:58:03Z","timestamp":1785445083008,"version":"3.56.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Glucocorticoids (GCs) are essential for the therapy of acute lymphoblastic leukemia (ALL), but glucocorticoid resistance remains a major clinical challenge, and its molecular mechanisms are not fully understood. This study aimed to investigate the role of ZFP36L2, an RNA-binding protein and potential driver gene in T-ALL, in regulating glucocorticoid sensitivity in ALL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      ZFP36L2 expression in ALL were reanalyzed from RNA sequencing data, and the correlation between ZFP36L2 expression and clinical outcomes in ALL patients was analyzed. ZFP36L2 was knocked down in T-ALL cells to observe its effects on glucocorticoid resistance and related signaling pathways. The effect of GCs combined with \u03b3-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) or MEK inhibitor trametinib on drug sensitivity was detected\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ZFP36L2 expression was significantly lower in T-ALL than in B-ALL, and low ZFP36L2 expression was associated with poor early disease responses and higher relapse risk in ALL. ZFP36L2 knockdown in T-ALL cell lines significantly increased glucocorticoid resistance, weakened glucocorticoid receptor upregulation, impaired apoptosis, reduced Bcl-2 interacting mediator of cell death induction, and repressed BCL2 downregulation. Moreover, ZFP36L2 was critical for glucocorticoid-mediated suppression of the NOTCH1\u2013HES1 and mitogen-activated protein kinase pathway. Notably, combined treatment with GCs and DAPT or trametinib enhanced drug sensitivity\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . Mechanistically, ZFP36L2 directly binds to the UAUUUAUU motifs in the 3\u2032 untranslated regions of BCL2, Bcl-2 interacting mediator of cell death, and NOTCH1 mRNAs, thereby regulating their stability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings demonstrate that ZFP36L2 is a potential regulator of glucocorticoid responsiveness in T-ALL. Combining GCs with DAPT or trametinib offers a potential therapeutic strategy for T-ALL patients, especially those with ZFP36L2 mutations or low ZFP36L2 expression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000607","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T21:00:18Z","timestamp":1781384418000},"page":"222-235","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Low expression of ZFP36L2 causes glucocorticoid resistance in childhood T-cell acute lymphoblastic leukemia"],"prefix":"10.1097","volume":"36","author":[{"given":"Yuening","family":"Xiang","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Birth Defects, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Birth Defects, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao","family":"Xie","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Birth Defects, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Birth Defects, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Birth Defects, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongsheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Birth Defects, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuiyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Children\u2019s Hospital of Soochow University, Suzhou"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinni","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Children\u2019s Hospital of Soochow University, Suzhou"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongsheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care, Quzhou Key Laboratory of Aging Biology and Longevity Medicine, Zhejiang-Germany Joint Laboratory on Lung Injury Repair and Regeneration, Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People\u2019s Hospital, Quzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Children\u2019s Hospital of Soochow University, Suzhou"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen Eng-Juh","family":"Yeoh","sequence":"additional","affiliation":[{"name":"Viva-University Children\u2019s Cancer Centre, KTP-National University Children\u2019s Medical Institute, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Hong Kong Children\u2019s Hospital, The Chinese University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowen","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, Shanghai"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoxiang","family":"Qian","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Birth Defects, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"R1-20260730","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1038\/s41586-024-07807-0","article-title":"The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.","volume":"632","author":"P\u00f6l\u00f6nen","year":"2024","journal-title":"Nature"},{"key":"R2-20260730","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/nature10725","article-title":"The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.","volume":"481","author":"Zhang","year":"2012","journal-title":"Nature"},{"key":"R3-20260730","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/ng.3909","article-title":"The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.","volume":"49","author":"Liu","year":"2017","journal-title":"Nat Genet"},{"key":"R4-20260730","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1182\/blood-2016-10-706465","article-title":"The genetics and molecular biology of T-ALL.","volume":"129","author":"Girardi","year":"2017","journal-title":"Blood"},{"key":"R5-20260730","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/nrc.2016.63","article-title":"The genetics and mechanisms of T cell acute lymphoblastic leukaemia.","volume":"16","author":"Belver","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"R6-20260730","doi-asserted-by":"crossref","first-page":"e142","DOI":"10.1016\/S1470-2045(19)30031-2","article-title":"Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia.","volume":"20","author":"Teachey","year":"2019","journal-title":"Lancet Oncol"},{"key":"R7-20260730","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/S1470-2045(10)70114-5","article-title":"Glucocorticoid use in acute lymphoblastic leukaemia.","volume":"11","author":"Inaba","year":"2010","journal-title":"Lancet Oncol"},{"key":"R8-20260730","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/s41419-018-1043-6","article-title":"Akt2 mediates glucocorticoid resistance in lymphoid malignancies through FoxO3a\/Bim axis and serves as a direct target for resistance reversal.","volume":"9","author":"Xie","year":"2019","journal-title":"Cell Death Dis"},{"key":"R9-20260730","doi-asserted-by":"crossref","DOI":"10.1186\/s12935-019-0940-9","article-title":"Haploinsufficiency of NR3C1 drives glucocorticoid resistance in adult acute lymphoblastic leukemia cells by down-regulating the mitochondrial apoptosis axis, and is sensitive to Bcl-2 blockage.","volume":"19","author":"Xiao","year":"2019","journal-title":"Cancer Cell Int"},{"key":"R10-20260730","doi-asserted-by":"crossref","first-page":"e513","DOI":"10.1097\/HS9.0000000000000513","article-title":"Recurrent NR3C1 aberrations at first diagnosis relate to steroid resistance in pediatric T-cell acute lymphoblastic leukemia patients.","volume":"5","author":"van der Zwet","year":"2021","journal-title":"HemaSphere"},{"key":"R11-20260730","doi-asserted-by":"crossref","first-page":"617937","DOI":"10.3389\/fonc.2021.617937","article-title":"Overcoming glucocorticoid resistance in acute lymphoblastic leukemia: repurposed drugs can improve the protocol.","volume":"11","author":"Olivas-Aguirre","year":"2021","journal-title":"Front Oncol"},{"key":"R12-20260730","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1093\/nar\/gku652","article-title":"ZFP36L1 and ZFP36L2 control LDLR mRNA stability via the ERK\u2013RSK pathway.","volume":"42","author":"Adachi","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"R13-20260730","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.3390\/cancers12061539","article-title":"The tristetraprolin family of RNA-binding proteins in cancer: progress and future prospects.","volume":"12","author":"Saini","year":"2020","journal-title":"Cancers (Basel)"},{"key":"R14-20260730","doi-asserted-by":"crossref","first-page":"2889","DOI":"10.4161\/cc.5.24.3539","article-title":"TIS11D is a candidate pro-apoptotic p53 target gene.","volume":"5","author":"Jackson","year":"2006","journal-title":"Cell Cycle"},{"key":"R15-20260730","doi-asserted-by":"crossref","DOI":"10.3892\/ijo_00000820","article-title":"Mutation in the RNA binding protein TIS11D\/ZFP36L2 is associated with the pathogenesis of acute leukemia.","volume":"38","author":"Iwanaga","year":"2010","journal-title":"Int J Oncol"},{"key":"R16-20260730","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1136\/gutjnl-2017-314607","article-title":"Identification of distinct mutational patterns and new driver genes in oesophageal squamous cell carcinomas and adenocarcinomas.","volume":"67","author":"Lin","year":"2018","journal-title":"Gut"},{"key":"R17-20260730","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/jso.25446","article-title":"Identification of a nine\u2010gene panel as a prognostic indicator for recurrence with muscle\u2010invasive bladder cancer.","volume":"119","author":"Han","year":"2019","journal-title":"J Surg Oncol"},{"key":"R18-20260730","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1136\/gutjnl-2020-323703","article-title":"Genomic evolution and diverse models of systemic metastases in colorectal cancer.","volume":"71","author":"Chen","year":"2022","journal-title":"Gut"},{"key":"R19-20260730","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/ni.1901","article-title":"Deletion of the RNA-binding proteins ZFP36L1 and ZFP36L2 leads to perturbed thymic development and T lymphoblastic leukemia.","volume":"11","author":"Hodson","year":"2010","journal-title":"Nat Immunol"},{"key":"R20-20260730","doi-asserted-by":"crossref","DOI":"10.1186\/s13046-022-02560-6","article-title":"Downregulation of Linc00173 increases BCL2 mRNA stability via the miR-1275\/PROCA1\/ZFP36L2 axis and induces acquired cisplatin resistance of lung adenocarcinoma.","volume":"42","author":"Tao","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"R21-20260730","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1101\/gr.209163.116","article-title":"Whole-transcriptome sequencing identifies a distinct subtype of acute lymphoblastic leukemia with predominant genomic abnormalities of EP300 and CREBBP.","volume":"27","author":"Qian","year":"2017","journal-title":"Genome Res"},{"key":"R22-20260730","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1182\/blood-2008-05-157842","article-title":"Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells.","volume":"113","author":"Hulleman","year":"2009","journal-title":"Blood"},{"key":"R23-20260730","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/2043-9113-1-36","article-title":"Elucidating the identity of resistance mechanisms to prednisolone exposure in acute lymphoblastic leukemia cells through transcriptomic analysis: a computational approach.","volume":"1","author":"Sifakis","year":"2011","journal-title":"J Clin Bioinforma"},{"key":"R24-20260730","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nm.1900","article-title":"Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.","volume":"15","author":"Real","year":"2009","journal-title":"Nat Med"},{"key":"R25-20260730","doi-asserted-by":"crossref","first-page":"188430","DOI":"10.1016\/j.bbcan.2020.188430","article-title":"Latest perspectives on glucocorticoid-induced apoptosis and resistance in lymphoid malignancies.","volume":"1874","author":"Clarisse","year":"2020","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"R26-20260730","doi-asserted-by":"crossref","first-page":"S41","DOI":"10.1038\/onc.2009.42","article-title":"Bim and Bmf in tissue homeostasis and malignant disease.","volume":"27","author":"Pi\u00f1on","year":"2009","journal-title":"Oncogene"},{"key":"R27-20260730","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.33057","article-title":"ZFP36 RNA-binding proteins restrain T cell activation and anti-viral immunity.","volume":"7","author":"Moore","year":"2018","journal-title":"eLife"},{"key":"R28-20260730","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nm.1900","article-title":"\u03b3-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.","volume":"15","author":"Real","year":"2008","journal-title":"Nat Med"},{"key":"R29-20260730","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/leu.2012.192","article-title":"Glucocorticoid sensitivity of T-cell lymphoblastic leukemia\/lymphoma is associated with glucocorticoid receptor-mediated inhibition of Notch1 expression.","volume":"27","author":"Cialfi","year":"2012","journal-title":"Leukemia"},{"key":"R30-20260730","doi-asserted-by":"crossref","first-page":"4489","DOI":"10.1038\/s41388-018-0251-y","article-title":"Notch-1-PTEN-ERK1\/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival.","volume":"37","author":"Baker","year":"2018","journal-title":"Oncogene"},{"key":"R31-20260730","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41419-018-0332-4","article-title":"Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity.","volume":"9","author":"Achuthan","year":"2018","journal-title":"Cell Death Dis"},{"key":"R32-20260730","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1038\/s41467-020-19075-3","article-title":"Combating acquired resistance to MAPK inhibitors in melanoma by targeting Abl1\/2-mediated reactivation of MEK\/ERK\/MYC signaling.","volume":"11","author":"Tripathi","year":"2020","journal-title":"Nat Commun"},{"key":"R33-20260730","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1111\/cas.15288","article-title":"MEK\/ERK\u2010mediated oncogenic signals promote secretion of extracellular vesicles by controlling lysosome function.","volume":"113","author":"Hikita","year":"2022","journal-title":"Cancer Sci"},{"key":"R34-20260730","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1182\/blood-2016-09-692582","article-title":"The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia.","volume":"129","author":"Sanchez-Martin","year":"2017","journal-title":"Blood"},{"key":"R35-20260730","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/leu.2012.285","article-title":"PI3K\/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response.","volume":"27","author":"Shepherd","year":"2012","journal-title":"Leukemia"},{"key":"R36-20260730","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1016\/j.jid.2016.07.024","article-title":"Notch1-MAPK signaling axis regulates CD133+ cancer stem cell-mediated melanoma growth and angiogenesis.","volume":"136","author":"Kumar","year":"2016","journal-title":"J Invest Dermatol"},{"key":"R37-20260730","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1096\/fj.05-4880fje","article-title":"Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K\/Akt pathways and requires MAML1.","volume":"20","author":"Liu","year":"2006","journal-title":"FASEB J"},{"key":"R38-20260730","doi-asserted-by":"crossref","first-page":"e70004","DOI":"10.1002\/mog2.70004","article-title":"WNT2 blockade augments antitumor immunity by attenuating myeloid-derived suppressor cells in colorectal cancer.","volume":"3","author":"Cui","year":"2024","journal-title":"MedComm \u2013 Oncology"},{"key":"R39-20260730","doi-asserted-by":"crossref","first-page":"100591","DOI":"10.1016\/j.blre.2019.100591","article-title":"Targeting steroid resistance in T-cell acute lymphoblastic leukemia.","volume":"38","author":"De Smedt","year":"2019","journal-title":"Blood Rev"}],"container-title":["Pharmacogenetics and Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1097\/FPC.0000000000000607","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T20:00:38Z","timestamp":1785441638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1097\/FPC.0000000000000607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":39,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1097\/fpc.0000000000000607","relation":{},"ISSN":["1744-6872","1744-6880"],"issn-type":[{"value":"1744-6872","type":"print"},{"value":"1744-6880","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]},"assertion":[{"value":"2026-03-30","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-14","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}