{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T06:38:10Z","timestamp":1772087890611,"version":"3.50.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Acute myeloid leukemia (AML) is a highly heterogeneous malignant hematological tumor, and its occurrence and development are closely related to immune evasion. Programmed death ligand 1 (PD-L1) is a key molecule mediating tumor immune escape, but its regulatory mechanism in AML has not been fully elucidated. The m6A demethylase ALKBH5 is highly expressed in various cancers, including AML, and promotes disease progression, but its specific role in modulating the PD-L1 axis and the immune microenvironment in AML remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed the expression and prognostic significance of ALKBH5 in AML by integrating BloodSpot, GEO, and TCGA databases, and performed functional enrichment and immune infiltration analyses. Bone marrow samples from 77 newly diagnosed AML patients and 13 healthy controls were collected for RT-qPCR validation, and their correlations with clinical features and PD-L1 expression were evaluated. ALKBH5 stable knockdown AML cell lines (THP-1 and MOLM-13) were constructed to assess cell proliferation, migration, and PD-L1 expression. T cell anti-tumor effects were evaluated using an AML cell and activated PBMC co-culture system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Bioinformatics analysis shows that ALKBH5 is significantly overexpressed in AML and is associated with poor prognosis and enrichment of immune related signaling pathways. Clinical sample testing further confirms that the level of ALKBH5 in AML patients is elevated, which is positively correlated with an increase in the proportion of primitive cells and PD-L1 expression.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments have shown that ALKBH5 knockdown significantly inhibits AML cell proliferation and migration, while reducing PD-L1 protein levels without affecting its mRNA expression, suggesting that it regulates PD-L1 through post transcriptional mechanisms. Co-culture experiments showed that ALKBH5 knockdown enhanced the proportion of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and secretion of IFN-\u03b3\/TNF-\u03b1, and reduced the survival rate of AML cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ALKBH5 may promote AML progression and immune escape through the upregulation of PD-L1 and modulation of T-cell function, which provides a theoretical basis for the development and screening of novel immunotherapeutic strategies for AML.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1781803","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T05:29:39Z","timestamp":1772083779000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ALKBH5 facilitates acute myeloid leukemia development and immune escape via PD-L1 regulation"],"prefix":"10.3389","volume":"16","author":[{"given":"Xin","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, The Sixth Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Sixth Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Sixth Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Le","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Sixth Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuemei","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Sixth Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangmei","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Laboratory Diagnostics, The First Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Sixth Affiliated Hospital of Harbin Medical University","place":["Harbin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019001124","article-title":"Highly multiplexed proteomic assessment of human bone marrow in acute myeloid leukemia","volume":"4","author":"Celik","year":"2020","journal-title":"Blood Adv"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2023.2228497","article-title":"Apicidin confers promising therapeutic effect on acute myeloid leukemia cells via increasing QPCT expression","volume":"24","author":"Liu","year":"2023","journal-title":"Cancer Biol Ther"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s13346-022-01189-4","article-title":"Modelling acute myeloid leukemia (AML): What\u2019s new? A transition from the classical to the modern","volume":"13","author":"Dozzo","year":"2023","journal-title":"Drug Delivery Transl Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-20-1030","article-title":"Anti-CD19 CAR T cells that secrete a biparatopic anti-CLEC12A bridging protein have potent activity against highly aggressive acute myeloid leukemia in vitro and in vivo","volume":"20","author":"Rennert","year":"2021","journal-title":"Mol Cancer Ther"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.3390\/biomedicines10081881","article-title":"NPM1-mutated patient-derived AML cells are more vulnerable to rac1 inhibition","volume":"10","author":"Hemsing","year":"2022","journal-title":"Biomedicines"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.16310","article-title":"Acute myeloid leukaemia and the immune system: implications for immunotherapy","volume":"188","author":"Barrett","year":"2020","journal-title":"Br J Haematol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113794","article-title":"ZEB1 shapes AML immunological niches, suppressing CD8 T cell activity while fostering Th17 cell expansion","volume":"43","author":"Bassani","year":"2024","journal-title":"Cell Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00213","article-title":"Targeting the immune microenvironment in acute myeloid leukemia: A focus on T cell immunity","volume":"8","author":"Lamble","year":"2018","journal-title":"Front Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.critrevonc.2016.04.020","article-title":"Harnessing the immune system in acute myeloid leukaemia","volume":"103","author":"Austin","year":"2016","journal-title":"Crit Rev Oncol Hematol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2022.100907","article-title":"Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1\/PD-L1 blockade","volume":"66","author":"Pang","year":"2023","journal-title":"Drug Resist Update"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.12.654","article-title":"PD-L1 on mast cells suppresses effector CD8(+) T-cell activation in the skin in murine contact hypersensitivity","volume":"148","author":"Hirano","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31896","article-title":"The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia","volume":"125","author":"Williams","year":"2019","journal-title":"Cancer"},{"key":"B13","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1182\/blood-2013-07-517987","article-title":"Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity","volume":"123","author":"Hossain","year":"2014","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.7534\/j.issn.1009-2137.2015.04.004","article-title":"Expression of programmed death ligand-1 (PD-L1) in human acute leukemia and its clinical significance","volume":"23","author":"Zhang","year":"2015","journal-title":"Zhongguo Shi Yan Xue Ye Xue Za Zhi"},{"key":"B15","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1186\/s13045-016-0350-6","article-title":"CD274 promotes cell cycle entry of leukemia-initiating cells through JNK\/Cyclin D2 signaling","volume":"9","author":"Fang","year":"2016","journal-title":"J Hematol Oncol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.355","article-title":"Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents","volume":"28","author":"Yang","year":"2014","journal-title":"Leukemia"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20112823","article-title":"High PD-L1 expression predicts for worse outcome of leukemia patients with concomitant NPM1 and FLT3 mutations","volume":"20","author":"Brodsk\u00e1","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B18","doi-asserted-by":"publisher","first-page":"3489","DOI":"10.3390\/cancers14143489","article-title":"N(6)-methyladenosine RNA-binding protein YTHDF1 in gastrointestinal cancers: function, molecular mechanism and clinical implication","volume":"14","author":"Chen","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1038\/s41419-021-04272-9","article-title":"METTL3-mediated mRNA N(6)-methyladenosine is required for oocyte and follicle development in mice","volume":"12","author":"Mu","year":"2021","journal-title":"Cell Death Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-0468","article-title":"M(6)A demethylase ALKBH5 regulates PD-L1 expression and tumor immunoenvironment in intrahepatic cholangiocarcinoma","volume":"81","author":"Qiu","year":"2021","journal-title":"Cancer Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-1456","article-title":"ALKBH5 facilitates hypoxia-induced paraspeckle assembly and IL8 secretion to generate an immunosuppressive tumor microenvironment","volume":"81","author":"Dong","year":"2021","journal-title":"Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.70149","article-title":"ALKBH5\/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression","volume":"18","author":"You","year":"2022","journal-title":"Int J Biol Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1918986117","article-title":"ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment","volume":"117","author":"Li","year":"2020","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B24","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.stem.2020.04.009","article-title":"RNA demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia","volume":"27","author":"Shen","year":"2020","journal-title":"Cell Stem Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.stem.2020.04.001","article-title":"Leukemogenic chromatin alterations promote AML leukemia stem cells via a KDM4C-ALKBH5-AXL signaling axis","volume":"27","author":"Wang","year":"2020","journal-title":"Cell Stem Cell"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e230","DOI":"10.1038\/bcj.2014.50","article-title":"The stimulation of PD-L1-specific cytotoxic T lymphocytes can both directly and indirectly enhance antileukemic immunity","volume":"4","author":"Ahmad","year":"2014","journal-title":"Blood Cancer J"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.781660","article-title":"Regulating histone deacetylase signaling pathways of myeloid-derived suppressor cells enhanced T cell-based immunotherapy","volume":"13","author":"Adeshakin","year":"2022","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"11444","DOI":"10.1038\/s41598-022-15020-0","article-title":"PD-L1 regulates cell proliferation and apoptosis in acute myeloid leukemia by activating PI3K-AKT signaling pathway","volume":"12","author":"Wang","year":"2022","journal-title":"Sci Rep"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114032","article-title":"A LATS2 and ALKBH5 positive feedback loop supports their oncogenic roles","volume":"43","author":"Cao","year":"2024","journal-title":"Cell Rep"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.972341","article-title":"Ovarian cancer subtypes based on the regulatory genes of RNA modifications: Novel prediction model of prognosis","volume":"13","author":"Zheng","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s13105-019-00690-8","article-title":"ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1","volume":"75","author":"Zhang","year":"2019","journal-title":"J Physiol Biochem"},{"key":"B32","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/s41420-022-01286-w","article-title":"ALKBH5 promotes PD-L1-mediated immune escape through m6A modification of ZDHHC3 in glioma","volume":"8","author":"Tang","year":"2022","journal-title":"Cell Death Discov"},{"key":"B33","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1186\/s13046-024-03073-0","article-title":"ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages","volume":"43","author":"Hua","year":"2024","journal-title":"J Exp Clin Cancer Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.04.032","article-title":"ALKBH5 drives immune suppression via targeting AXIN2 to promote colorectal cancer and is a target for boosting immunotherapy","volume":"165","author":"Zhai","year":"2023","journal-title":"Gastroenterology"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1781803\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T05:29:41Z","timestamp":1772083781000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1781803\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,26]]},"references-count":34,"alternative-id":["10.3389\/fonc.2026.1781803"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1781803","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,26]]},"article-number":"1781803"}}