{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T04:46:07Z","timestamp":1779338767225,"version":"3.51.4"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA266472"],"award-info":[{"award-number":["R01CA266472"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Hypomethylating agents (HMAs), such as 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia (AML). Despite providing significant extensions in survival when used alone or in combination with BCL-2 inhibitors, resistance and eventual relapse is observed. Reported mechanisms of these outcomes are inconsistent when focusing on leukemic populations within bone marrow, indicating a need for studies on the impact of HMAs on non-leukemic cells in the blood and other tissue compartments.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Whole blood and spleens from vehicle- or AZA-treated mice implanted with the syngeneic AML line C1498 were transcriptionally profiled using a comprehensive panel of immune-related gene probes. Publicly available RNAseq data from blood of AZA-responsive, human AML patients were analyzed compared to matched, pre-treatment samples. Genes differentially expressed between vehicle- and AZA-treated (mouse) or pre- and post-AZA treatment (human) samples were analyzed for statistical overrepresentation in gene ontologies using Fisher\u2019s one-tailed <jats:italic>t<\/jats:italic>-test. Pathological analyses of various tissues in AML relapsed, AZA-responsive mice were compared to the corresponding tissues in vehicle-treated mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We observed hematologic recovery in the peripheral blood of AZA-treated groups, versus vehicle control, that was associated with significant extensions in survival. Transcriptional analysis of AZA-treated samples revealed decreased cell type scores for suppressive subsets and increased pathway scores for T and B cell functions. Comparisons of gene ontology annotations enriched from genes differentially regulated by AZA in human and mouse blood samples revealed overlap in numerous biological pathways including adhesion, thrombosis, and angiogenesis. Consistently, C1498 permeated the liver at end-stage disease in vehicle-treated mice, while AZA treatment limited their spread to just outside the bone after relapse.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>AZA-induced differences in C1498 spread could be a result of gene expression changes in adhesion, platelet aggregation and\/or angiogenesis in non-leukemic compartments; however, further mechanistic studies must be done to confirm a direct link between modulated genes and disease manifestation. Overall, these studies provide rationale for expanding the exploration of biomarkers and therapeutic targets to include normal immune cells in blood, spleen, or other microenvironments of AML patients treated with HMA, rather than limiting studies to the bone marrow and leukemic blasts.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s10020-025-01233-2","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T08:59:33Z","timestamp":1747126773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcriptomic analysis of non-leukemic cell subsets in azacytidine-responsive AML highlights pathways associated with adhesion, platelet aggregation, and angiogenesis in mice and humans"],"prefix":"10.1186","volume":"31","author":[{"given":"Nancy D.","family":"Ebelt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suvithanandhini","family":"Loganathan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lara C.","family":"Avsharian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin R.","family":"Manuel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"1233_CR1","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.ccr.2012.06.032","volume":"22","author":"O Abdel-Wahab","year":"2012","unstructured":"Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22:180\u201393.","journal-title":"Cancer Cell"},{"key":"1233_CR2","volume":"14","author":"KA Abuelgasim","year":"2020","unstructured":"Abuelgasim KA, Albuhayri B, Munshi R, et al. Impact of age and induction therapy on outcome of 180 adult patients with acute myeloid leukemia; retrospective analysis and literature review. Leuk Res Rep. 2020;14: 100206.","journal-title":"Leuk Res Rep"},{"key":"1233_CR3","first-page":"14042","volume":"23","author":"A Alexandraki","year":"2022","unstructured":"Alexandraki A, Strati K. Decitabine Treatment Induces a Viral Mimicry Response in Cervical Cancer Cells and Further Sensitizes Cells to Chemotherapy. 2022;23:14042.","journal-title":"Decitabine Treatment Induces a Viral Mimicry Response in Cervical Cancer Cells and Further Sensitizes Cells to Chemotherapy"},{"key":"1233_CR4","doi-asserted-by":"publisher","first-page":"3095","DOI":"10.3389\/fimmu.2019.03095","volume":"10","author":"K Anderson","year":"2019","unstructured":"Anderson K, Ryan N, Volpedo G, Varikuti S, Satoskar AR, Oghumu S. Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC. Front Immunol. 2019;10:3095.","journal-title":"Front Immunol"},{"key":"1233_CR5","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1038\/bmt.2012.256","volume":"48","author":"A Antar","year":"2013","unstructured":"Antar A, Otrock ZK, Kharfan-Dabaja M, et al. Azacitidine in the treatment of extramedullary relapse of AML after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2013;48:994\u20135.","journal-title":"Bone Marrow Transplant"},{"key":"1233_CR6","doi-asserted-by":"publisher","first-page":"3900","DOI":"10.1182\/bloodadvances.2020003841","volume":"5","author":"AK Bankova","year":"2021","unstructured":"Bankova AK, Pang WW, Velasco BJ, Long-Boyle JR, Shizuru JA. 5-Azacytidine depletes HSCs and synergizes with an anti-CD117 antibody to augment donor engraftment in immunocompetent mice. Blood Adv. 2021;5:3900\u201312.","journal-title":"Blood Adv"},{"key":"1233_CR7","doi-asserted-by":"publisher","first-page":"3756","DOI":"10.1182\/blood.V122.21.3756.3756","volume":"122","author":"SR Bohl","year":"2013","unstructured":"Bohl SR, Claus R, Dolnik A, et al. Decitabine Response Associated Gene Expression Patterns In Acute Myeloid Leukemia (AML). Blood. 2013;122:3756.","journal-title":"Blood"},{"key":"1233_CR8","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3389\/fimmu.2017.00106","volume":"8","author":"AK Brenner","year":"2017","unstructured":"Brenner AK, Nepstad I, Bruserud \u00d8. Mesenchymal Stem Cells Support Survival and Proliferation of Primary Human Acute Myeloid Leukemia Cells through Heterogeneous Molecular Mechanisms. Front Immunol. 2017;8:106.","journal-title":"Front Immunol"},{"key":"1233_CR9","doi-asserted-by":"publisher","unstructured":"Chang KH, Zhang W, Basyal M, et al. AML-337: Targeting E-Selectin with GMI-1271 Overcomes Microenvironment-Mediated Resistance to Venetoclax\/HMA Therapy: Clin Lymphoma Myeloma Leuk. 2020 Sep;20:S205. https:\/\/doi.org\/10.1016\/S2152-2650(20)30760-6. Epub 2020 Dec 9.","DOI":"10.1016\/S2152-2650(20)30760-6"},{"key":"1233_CR10","doi-asserted-by":"publisher","first-page":"2707","DOI":"10.1158\/2159-8290.CD-21-0506","volume":"11","author":"R Chen","year":"2021","unstructured":"Chen R, Ishak CA, De Carvalho DD. Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy and Cellular Homeostasis. Cancer Discov. 2021;11:2707\u201325.","journal-title":"Cancer Discov"},{"key":"1233_CR11","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41408-018-0094-3","volume":"8","author":"WY Cheng","year":"2018","unstructured":"Cheng WY, Zhu YM, Liu Z, et al. Impact of blood count recovery on outcomes of acute myeloid leukemia patients achieving morphologic leukemia-free state. Blood Cancer J. 2018;8:53.","journal-title":"Blood Cancer J"},{"key":"1233_CR12","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1016\/j.cell.2015.07.011","volume":"162","author":"B Chiappinelli Katherine","year":"2015","unstructured":"Chiappinelli Katherine B, Strissel Pamela L, Desrichard A, et al. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell. 2015;162:974\u201386.","journal-title":"Cell"},{"key":"1233_CR13","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/s13148-019-0704-3","volume":"11","author":"W Chung","year":"2019","unstructured":"Chung W, Kelly AD, Kropf P, et al. Genomic and epigenomic predictors of response to guadecitabine in relapsed\/refractory acute myelogenous leukemia. Clin Epigenetics. 2019;11:106.","journal-title":"Clin Epigenetics"},{"key":"1233_CR14","doi-asserted-by":"publisher","first-page":"D138","DOI":"10.1093\/nar\/gkad965","volume":"52","author":"E Clough","year":"2023","unstructured":"Clough E, Barrett T, Wilhite SE, et al. NCBI GEO: archive for gene expression and epigenomics data sets: 23-year update. Nucleic Acids Res. 2023;52:D138\u201344.","journal-title":"Nucleic Acids Res"},{"key":"1233_CR15","doi-asserted-by":"crossref","unstructured":"Darwish NHE, Glinsky GV, Sudha T, Mousa SA. Targeting Thyrointegrin \u03b1v\u03b23 Using Fluorobenzyl Polyethylene Glycol Conjugated Tetraiodothyroacetic Acid (NP751) in Acute Myeloid Leukemia. 2022;11.","DOI":"10.3389\/fonc.2021.793810"},{"key":"1233_CR16","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1182\/blood-2021-153638","volume":"138","author":"N Daver","year":"2021","unstructured":"Daver N, Konopleva M, Maiti A, et al. Phase I\/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed Older\/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed\/Refractory (R\/R) AML. Blood. 2021;138:371.","journal-title":"Blood"},{"key":"1233_CR17","first-page":"617","volume":"383","author":"CD DiNardo","year":"2020","unstructured":"DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. 2020;383:617\u201329.","journal-title":"Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia"},{"key":"1233_CR18","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1158\/2159-8290.CD-19-0106","volume":"9","author":"C Duy","year":"2019","unstructured":"Duy C, Teater M, Garrett-Bakelman FE, et al. Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML. Cancer Discov. 2019;9:872\u201389.","journal-title":"Cancer Discov"},{"key":"1233_CR19","doi-asserted-by":"publisher","first-page":"538","DOI":"10.3389\/fimmu.2020.00538","volume":"11","author":"ND Ebelt","year":"2020","unstructured":"Ebelt ND, Zuniga E, Johnson BL, Diamond DJ, Manuel ER. 5-Azacytidine Potentiates Anti-tumor Immunity in a Model of Pancreatic Ductal Adenocarcinoma. Front Immunol. 2020;11:538.","journal-title":"Front Immunol"},{"key":"1233_CR20","doi-asserted-by":"crossref","unstructured":"Ebelt ND, Manuel ER. 5-Azacytidine-Mediated Modulation of the Immune Microenvironment in Murine Acute Myeloid Leukemia. Cancers 2022;15.","DOI":"10.3390\/cancers15010118"},{"key":"1233_CR21","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/nar\/30.1.207","volume":"30","author":"R Edgar","year":"2002","unstructured":"Edgar R, Domrachev M, Lash AE. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30:207\u201310.","journal-title":"Nucleic Acids Res"},{"key":"1233_CR22","doi-asserted-by":"publisher","first-page":"2764","DOI":"10.1182\/blood-2009-02-203547","volume":"114","author":"TE Fandy","year":"2009","unstructured":"Fandy TE, Herman JG, Kerns P, et al. Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies. Blood. 2009;114:2764\u201373.","journal-title":"Blood"},{"key":"1233_CR23","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.ccr.2010.11.015","volume":"18","author":"ME Figueroa","year":"2010","unstructured":"Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553\u201367.","journal-title":"Cancer Cell"},{"key":"1233_CR24","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1016\/j.biopha.2017.11.040","volume":"97","author":"K Fraczkowska","year":"2018","unstructured":"Fraczkowska K, Bacia M, Przyby\u0142o M, et al. Alterations of biomechanics in cancer and normal cells induced by doxorubicin. Biomed Pharmacother. 2018;97:1195\u2013203.","journal-title":"Biomed Pharmacother"},{"key":"1233_CR25","doi-asserted-by":"crossref","unstructured":"Ga\u00f1\u00e1n-G\u00f3mez I, Ogoti Y, Marchesini M, et al. Effect of Azacytidine on the Hematopoietic Stem and Progenitor Cell Compartments of MDS Mouse Models: Unveiling the Mechanisms of Remission and Relapse. Blood 2015;126:2852-.","DOI":"10.1182\/blood.V126.23.2852.2852"},{"key":"1233_CR26","doi-asserted-by":"crossref","unstructured":"Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. 2013;368:2059\u201374.","DOI":"10.1056\/NEJMoa1301689"},{"key":"1233_CR27","doi-asserted-by":"crossref","unstructured":"Gruszka AM, Valli D, Restelli C, Alcalay M. Adhesion Deregulation in Acute Myeloid Leukaemia. Cells 2019;8.","DOI":"10.3390\/cells8010066"},{"key":"1233_CR28","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1016\/j.injury.2011.03.035","volume":"42","author":"KD Hankenson","year":"2011","unstructured":"Hankenson KD, Dishowitz M, Gray C, Schenker M. Angiogenesis in bone regeneration. Injury. 2011;42:556\u201361.","journal-title":"Injury"},{"key":"1233_CR29","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1179\/1607845413Y.0000000139","volume":"19","author":"H Haouas","year":"2014","unstructured":"Haouas H. Angiogenesis and acute myeloid leukemia. Hematology. 2014;19:311\u201323.","journal-title":"Hematology"},{"key":"1233_CR30","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.ccr.2012.03.014","volume":"21","author":"WJ Harris","year":"2012","unstructured":"Harris WJ, Huang X, Lynch JT, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21:473\u201387.","journal-title":"Cancer Cell"},{"key":"1233_CR31","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1186\/1471-2164-9-488","volume":"9","author":"T Hulsen","year":"2008","unstructured":"Hulsen T, de Vlieg J, Alkema W. BioVenn \u2013 a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams. BMC Genomics. 2008;9:488.","journal-title":"BMC Genomics"},{"key":"1233_CR32","first-page":"1082","volume":"109","author":"DV Jeyaraju","year":"2024","unstructured":"Jeyaraju DV, Alapa M, Polonskaia A, et al. Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase. Haematologica. 2024;109:1082\u201394.","journal-title":"Haematologica"},{"key":"1233_CR33","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1023\/A:1008255511404","volume":"9","author":"T Karakas","year":"1998","unstructured":"Karakas T, Maurer U, Weidmann E, Miething CC, Hoelzer D, Bergmann L. High expression of bcl-2 mRNA as a determinant of poor prognosis in acute myeloid leukemia. Annals of Oncology\u202f: Official Journal of the European Society for Medical Oncology \/ ESMO. 1998;9:159\u201365.","journal-title":"Annals of Oncology : Official Journal of the European Society for Medical Oncology \/ ESMO"},{"key":"1233_CR34","doi-asserted-by":"crossref","unstructured":"Katagiri T, Ushiki T, Masuko M, et al. Successful 5-azacytidine treatment of myeloid sarcoma and leukemia cutis associated with myelodysplastic syndrome: A case report and literature review. Medicine 2017;96.","DOI":"10.1097\/MD.0000000000007975"},{"key":"1233_CR35","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.2165\/11209430-000000000-00000","volume":"72","author":"GM Keating","year":"2012","unstructured":"Keating GM. Azacitidine: a review of its use in the management of myelodysplastic syndromes\/acute myeloid leukaemia. Drugs. 2012;72:1111\u201336.","journal-title":"Drugs"},{"key":"1233_CR36","doi-asserted-by":"crossref","unstructured":"Kobayashi N, Oda T, Takizawa M, et al. Integrin \u03b17 and Extracellular Matrix Laminin 211 Interaction Promotes Proliferation of Acute Myeloid Leukemia Cells and Is Associated with Granulocytic Sarcoma. Cancers 2020;12.","DOI":"10.3390\/cancers12020363"},{"key":"1233_CR37","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1182\/blood-2018-03-828269","volume":"132","author":"M Konopleva","year":"2018","unstructured":"Konopleva M, Letai A. BCL-2 inhibition in AML: an unexpected bonus? Blood. 2018;132:1007\u201312.","journal-title":"Blood"},{"key":"1233_CR38","first-page":"1758","volume":"5","author":"SM Kornblau","year":"1999","unstructured":"Kornblau SM, Thall PF, Estrov Z, et al. The prognostic impact of BCL2 protein expression in acute myelogenous leukemia varies with cytogenetics. Clinical Cancer Research\u202f: an Official Journal of the American Association for Cancer Research. 1999;5:1758\u201366.","journal-title":"Clinical Cancer Research : an Official Journal of the American Association for Cancer Research"},{"key":"1233_CR39","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1182\/bloodadvances.2017013391","volume":"2","author":"TJ Kovacsovics","year":"2018","unstructured":"Kovacsovics TJ, Mims A, Salama ME, et al. Combination of the low anticoagulant heparin CX-01 with chemotherapy for the treatment of acute myeloid leukemia. Blood Adv. 2018;2:381\u20139.","journal-title":"Blood Adv"},{"key":"1233_CR40","doi-asserted-by":"crossref","unstructured":"Krenn PW, Montanez E, Costell M, F\u00e4ssler R. Chapter Six - Integrins, anchors and signal transducers of hematopoietic stem cells during development and in adulthood. In: Soriano PM, ed. Current Topics in Developmental Biology: Academic Press; 2022:203\u201361.","DOI":"10.1016\/bs.ctdb.2022.02.009"},{"key":"1233_CR41","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1016\/j.exphem.2016.07.012","volume":"44","author":"I Laverdi\u00e8re","year":"2016","unstructured":"Laverdi\u00e8re I, Boileau M, Herold T, et al. Complement cascade gene expression defines novel prognostic subgroups of acute myeloid leukemia. Exp Hematol. 2016;44:1039-43.e10.","journal-title":"Exp Hematol"},{"key":"1233_CR42","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006627","volume":"2","author":"PR Lawler","year":"2012","unstructured":"Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med. 2012;2: a006627.","journal-title":"Cold Spring Harb Perspect Med"},{"key":"1233_CR43","doi-asserted-by":"crossref","unstructured":"Layssol-Lamour CJ, Sarry JE, Braun JD, Trumel C, Bourges-Abella NH. Reference Values for Hematology, Plasma Biochemistry, Bone Marrow Cytology and Bone Histology of NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)\/ SzJ Immunodeficient Mice. J Am Assoc Lab Anim Sci 2021;60:4\u201317.","DOI":"10.30802\/AALAS-JAALAS-20-000020"},{"key":"1233_CR44","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research N, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368:2059\u201374.","DOI":"10.1056\/NEJMoa1301689"},{"key":"1233_CR45","doi-asserted-by":"publisher","first-page":"20230840","DOI":"10.1515\/med-2023-0840","volume":"19","author":"A Li","year":"2024","unstructured":"Li A, Wu J. High STAT4 expression correlates with poor prognosis in acute myeloid leukemia and facilitates disease progression by upregulating VEGFA expression. Open Medicine (Warsaw, Poland). 2024;19:20230840.","journal-title":"Open Medicine (Warsaw, Poland)"},{"key":"1233_CR46","doi-asserted-by":"publisher","first-page":"W199","DOI":"10.1093\/nar\/gkz401","volume":"47","author":"Y Liao","year":"2019","unstructured":"Liao Y, Wang J, Jaehnig EJ, Shi Z, Zhang B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 2019;47:W199\u2013205.","journal-title":"Nucleic Acids Res"},{"key":"1233_CR47","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1182\/blood-2009-06-230474","volume":"116","author":"GJ Madlambayan","year":"2010","unstructured":"Madlambayan GJ, Meacham AM, Hosaka K, et al. Leukemia regression by vascular disruption and antiangiogenic therapy. Blood. 2010;116:1539\u201347.","journal-title":"Blood"},{"key":"1233_CR48","doi-asserted-by":"publisher","first-page":"3641","DOI":"10.1016\/j.celrep.2018.03.012","volume":"22","author":"A Maiques-Diaz","year":"2018","unstructured":"Maiques-Diaz A, Spencer GJ, Lynch JT, et al. Enhancer Activation by Pharmacologic Displacement of LSD1 from GFI1 Induces Differentiation in Acute Myeloid Leukemia. Cell Rep. 2018;22:3641\u201359.","journal-title":"Cell Rep"},{"key":"1233_CR49","first-page":"53","volume":"6","author":"P Malik","year":"2014","unstructured":"Malik P, Cashen AF. Decitabine in the treatment of acute myeloid leukemia in elderly patients. Cancer Manag Res. 2014;6:53\u201361.","journal-title":"Cancer Manag Res"},{"key":"1233_CR50","doi-asserted-by":"publisher","first-page":"2731","DOI":"10.4049\/jimmunol.172.5.2731","volume":"172","author":"J Mestas","year":"2004","unstructured":"Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731\u20138.","journal-title":"J Immunol"},{"key":"1233_CR51","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ccr.2013.05.004","volume":"24","author":"G Miller Peter","year":"2013","unstructured":"Miller Peter G, Al-Shahrour F, Hartwell Kimberly A, et al. In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling. Cancer Cell. 2013;24:45\u201358.","journal-title":"Cancer Cell"},{"key":"1233_CR52","doi-asserted-by":"crossref","unstructured":"Mopin A, Driss V, Brinster C. A Detailed Protocol for Characterizing the Murine C1498 Cell Line and its Associated Leukemia Mouse Model. Journal of visualized experiments : JoVE 2016.","DOI":"10.3791\/54270-v"},{"key":"1233_CR53","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1111\/bjh.15818","volume":"185","author":"MR Nahas","year":"2019","unstructured":"Nahas MR, Stroopinsky D, Rosenblatt J, et al. Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia (AML) and enhances the immunogenicity of a dendritic cell\/AML vaccine. Br J Haematol. 2019;185:679\u201390.","journal-title":"Br J Haematol"},{"key":"1233_CR54","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1158\/2643-3230.BCD-23-0020","volume":"4","author":"A Nelde","year":"2023","unstructured":"Nelde A, Schuster H, Heitmann JS, et al. Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells. Blood Cancer Discovery. 2023;4:468\u201389.","journal-title":"Blood Cancer Discovery"},{"key":"1233_CR55","doi-asserted-by":"publisher","first-page":"8799","DOI":"10.1182\/blood-2022-167902","volume":"140","author":"H Ogana","year":"2022","unstructured":"Ogana H, Hurwitz S, Wan Z, et al. The Role of Integrin Beta-1 in the Chemoresistance of Acute Myeloid Leukemia. Blood. 2022;140:8799\u2013800.","journal-title":"Blood"},{"key":"1233_CR56","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1111\/bph.16149","volume":"181","author":"HA Ogana","year":"2024","unstructured":"Ogana HA, Hurwitz S, Wei N, et al. Targeting integrins in drug-resistant acute myeloid leukaemia. Br J Pharmacol. 2024;181:295\u2013316.","journal-title":"Br J Pharmacol"},{"key":"1233_CR57","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1158\/0008-5472.CAN-19-1696","volume":"80","author":"H Ohtani","year":"2020","unstructured":"Ohtani H, \u00d8rskov AD, Helbo AS, et al. Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-Azacytidine. Can Res. 2020;80:2441\u201350.","journal-title":"Can Res"},{"key":"1233_CR58","doi-asserted-by":"crossref","unstructured":"Palmieri R, Paterno G, De Bellis E, et al. Therapeutic Choice in Older Patients with Acute Myeloid Leukemia: A Matter of Fitness. Cancers 2020;12.","DOI":"10.3390\/cancers12010120"},{"key":"1233_CR59","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1038\/s41375-024-02217-7","volume":"38","author":"A Perzolli","year":"2024","unstructured":"Perzolli A, Koedijk JB, Zwaan CM, Heidenreich O. Targeting the innate immune system in pediatric and adult AML. Leukemia. 2024;38:1191\u2013201.","journal-title":"Leukemia"},{"key":"1233_CR60","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1097\/MOH.0000000000000626","volume":"28","author":"JS Romer-Seibert","year":"2021","unstructured":"Romer-Seibert JS, Meyer SE. Genetic heterogeneity and clonal evolution in acute myeloid leukemia. Curr Opin Hematol. 2021;28:64\u201370.","journal-title":"Curr Opin Hematol"},{"key":"1233_CR61","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1016\/j.cell.2015.07.056","volume":"162","author":"D Roulois","year":"2015","unstructured":"Roulois D, Loo Yau H, Singhania R, et al. DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts. Cell. 2015;162:961\u201373.","journal-title":"Cell"},{"key":"1233_CR62","doi-asserted-by":"publisher","first-page":"3914","DOI":"10.1158\/0008-5472.CAN-03-3991","volume":"64","author":"MG Sauer","year":"2004","unstructured":"Sauer MG, Ericson ME, Weigel BJ, et al. A Novel System for Simultaneous in Vivo Tracking and Biological Assessment of Leukemia Cells and ex Vivo Generated Leukemia-Reactive Cytotoxic T Cells. Can Res. 2004;64:3914\u201321.","journal-title":"Can Res"},{"key":"1233_CR63","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1186\/s13148-023-01580-z","volume":"15","author":"M Schmutz","year":"2023","unstructured":"Schmutz M, Zucknick M, Schlenk RF, et al. Predictive value of DNA methylation patterns in AML patients treated with an azacytidine containing induction regimen. Clin Epigenetics. 2023;15:171.","journal-title":"Clin Epigenetics"},{"key":"1233_CR64","doi-asserted-by":"publisher","first-page":"S246","DOI":"10.1016\/S2152-2650(22)01286-1","volume":"22","author":"A Shatilova","year":"2022","unstructured":"Shatilova A, Budaeva I, Motorin D, et al. AML-396 Venetoclax-Containing Regimens Improve Outcomes of Intensive Treatment and Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Extramedullary Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk. 2022;22:S246.","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"1233_CR65","doi-asserted-by":"publisher","first-page":"7143","DOI":"10.4049\/jimmunol.175.11.7143","volume":"175","author":"HJ Shin","year":"2005","unstructured":"Shin HJ, Park HY, Jeong SJ, et al. STAT4 expression in human T cells is regulated by DNA methylation but not by promoter polymorphism. J Immunol. 2005;175:7143\u201350.","journal-title":"J Immunol"},{"key":"1233_CR66","doi-asserted-by":"publisher","first-page":"2697","DOI":"10.1002\/cncr.25774","volume":"117","author":"LR Silverman","year":"2011","unstructured":"Silverman LR, Fenaux P, Mufti GJ, et al. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer. 2011;117:2697\u2013702.","journal-title":"Cancer"},{"key":"1233_CR67","doi-asserted-by":"publisher","first-page":"53","DOI":"10.3390\/molecules14010053","volume":"14","author":"I Spasojevi\u0107","year":"2008","unstructured":"Spasojevi\u0107 I, Jeli\u0107 S, Zakrzewska J, Baci\u0107 G. Decreased oxygen transfer capacity of erythrocytes as a cause of 5-fluorouracil related ischemia. Molecules (Basel, Switzerland). 2008;14:53\u201367.","journal-title":"Molecules (Basel, Switzerland)"},{"key":"1233_CR68","doi-asserted-by":"publisher","first-page":"3484","DOI":"10.1158\/0008-5472.CAN-15-2663","volume":"76","author":"X Su","year":"2016","unstructured":"Su X, Esser AK, Amend SR, et al. Antagonizing Integrin \u03b23 Increases Immunosuppression in Cancer. Can Res. 2016;76:3484\u201395.","journal-title":"Can Res"},{"key":"1233_CR69","doi-asserted-by":"publisher","first-page":"28812","DOI":"10.18632\/oncotarget.15807","volume":"8","author":"M Tobiasson","year":"2017","unstructured":"Tobiasson M, Abdulkadir H, Lennartsson A, et al. Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive\/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease. Oncotarget. 2017;8:28812\u201325.","journal-title":"Oncotarget"},{"key":"1233_CR70","doi-asserted-by":"publisher","first-page":"1861","DOI":"10.1007\/s00277-012-1537-8","volume":"91","author":"T Tsao","year":"2012","unstructured":"Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012;91:1861\u201370.","journal-title":"Ann Hematol"},{"key":"1233_CR71","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1182\/blood-2011-02-335430","volume":"119","author":"T Umemoto","year":"2012","unstructured":"Umemoto T, Yamato M, Ishihara J, et al. Integrin-\u03b1v\u03b23 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells. Blood. 2012;119:83\u201394.","journal-title":"Blood"},{"key":"1233_CR72","doi-asserted-by":"publisher","first-page":"63","DOI":"10.21037\/atm-23-1824","volume":"12","author":"AP Urs","year":"2024","unstructured":"Urs AP, Goda C, Kulkarni R. Remodeling of the bone marrow microenvironment during acute myeloid leukemia progression. Annals of Translational Medicine. 2024;12:63.","journal-title":"Annals of Translational Medicine"},{"issue":"1265\u201381","key":"1233_CR73","volume":"176","author":"P van Galen","year":"2019","unstructured":"van Galen P, Hovestadt V, Wadsworth Ii MH, et al. Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity. Cell. 2019;176(1265\u201381): e24.","journal-title":"Cell"},{"key":"1233_CR74","doi-asserted-by":"publisher","first-page":"613","DOI":"10.3324\/haematol.2013.099549","volume":"99","author":"MT Voso","year":"2014","unstructured":"Voso MT, Santini V, Fabiani E, et al. Why methylation is not a marker predictive of response to hypomethylating agents. Haematologica. 2014;99:613\u20139.","journal-title":"Haematologica"},{"key":"1233_CR75","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s12935-024-03271-y","volume":"24","author":"X Wan","year":"2024","unstructured":"Wan X, Wang J, Fang F, et al. Super enhancer related gene ANP32B promotes the proliferation of acute myeloid leukemia by enhancing MYC through histone acetylation. Cancer Cell Int. 2024;24:81.","journal-title":"Cancer Cell Int"},{"key":"1233_CR76","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.723001","volume":"12","author":"J Wang","year":"2021","unstructured":"Wang J, Uddin MN, Hao JP, et al. Identification of Potential Novel Prognosis-Related Genes Through Transcriptome Sequencing, Bioinformatics Analysis, and Clinical Validation in Acute Myeloid Leukemia. Front Genet. 2021;12: 723001.","journal-title":"Front Genet"},{"key":"1233_CR77","doi-asserted-by":"publisher","first-page":"3447","DOI":"10.1182\/bloodadvances.2018022053","volume":"2","author":"C Wenk","year":"2018","unstructured":"Wenk C, Garz AK, Grath S, et al. Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis. Blood Adv. 2018;2:3447\u201361.","journal-title":"Blood Adv"},{"key":"1233_CR78","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s12964-017-0168-z","volume":"15","author":"F Wolff","year":"2017","unstructured":"Wolff F, Leisch M, Greil R, Risch A, Pleyer L. The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation. Cell Commun Signal. 2017;15:13.","journal-title":"Cell Commun Signal"},{"key":"1233_CR79","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.624742","volume":"11","author":"KK Wong","year":"2021","unstructured":"Wong KK, Hassan R, Yaacob NS. Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes. Front Oncol. 2021;11: 624742.","journal-title":"Front Oncol"},{"key":"1233_CR80","first-page":"4898","volume":"14","author":"X Wu","year":"2022","unstructured":"Wu X, Li S, Chen D, et al. An inflammatory response-related gene signature associated with immune status and prognosis of acute myeloid leukemia. American Journal of Translational Research. 2022;14:4898\u2013917.","journal-title":"American Journal of Translational Research"},{"key":"1233_CR81","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.751834","volume":"11","author":"Y Xiao","year":"2021","unstructured":"Xiao Y, Chen J, Wang J, et al. Acute Myeloid Leukemia Epigenetic Immune Escape From Nature Killer Cells by ICAM-1. Front Oncol. 2021;11: 751834.","journal-title":"Front Oncol"},{"key":"1233_CR82","doi-asserted-by":"publisher","first-page":"40387","DOI":"10.18632\/oncotarget.9617","volume":"7","author":"H Yi","year":"2016","unstructured":"Yi H, Zeng D, Shen Z, et al. Integrin alphavbeta3 enhances beta-catenin signaling in acute myeloid leukemia harboring Fms-like tyrosine kinase-3 internal tandem duplication mutations: implications for microenvironment influence on sorafenib sensitivity. Oncotarget. 2016;7:40387\u201397.","journal-title":"Oncotarget"},{"key":"1233_CR83","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.cca.2022.09.015","volume":"536","author":"L Zhang","year":"2022","unstructured":"Zhang L, Liu J, Qin X, Liu W. Platelet-Acute Leukemia Interactions. Clin Chim Acta. 2022;536:29\u201338.","journal-title":"Clin Chim Acta"},{"key":"1233_CR84","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.3389\/fonc.2019.01567","volume":"9","author":"L Zhu","year":"2019","unstructured":"Zhu L, Li Q, Wang X, et al. THBS1 Is a Novel Serum Prognostic Factors of Acute Myeloid Leukemia. Front Oncol. 2019;9:1567.","journal-title":"Front Oncol"}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01233-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-025-01233-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-025-01233-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T21:04:28Z","timestamp":1747170268000},"score":1,"resource":{"primary":{"URL":"https:\/\/molmed.biomedcentral.com\/articles\/10.1186\/s10020-025-01233-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,13]]},"references-count":84,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1233"],"URL":"https:\/\/doi.org\/10.1186\/s10020-025-01233-2","relation":{},"ISSN":["1528-3658"],"issn-type":[{"value":"1528-3658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,13]]},"assertion":[{"value":"18 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The animal study protocol was approved by the Institutional Animal Care and Use Committee (IACUC) (Protocol no. 17128, approved 4 March 2024). All experiments were performed in accordance with the IACUC protocol.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors confirm their consent for publication of the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"185"}}