{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T11:40:23Z","timestamp":1793706023033,"version":"4.6.1"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"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:p>Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and the second most common in children. Despite the introduction of targeted therapies, AML survival rates have shown limited improvement, particularly among older patients. This study explored personalized treatment strategies for AML by proposing a novel subtyping method. Through unsupervised clustering based on the enrichment scores of 14 pathways related to metabolism, immunity, DNA repair, and oncogenic signaling, we identified three AML subtypes: DNA repair (DR), immune-enriched (ImE), and immune-deprived (ImD), consistent in four independent datasets. DR is marked by high expression of DNA repair and metabolic pathways, high stemness and proliferation potential, as well as high sensitivity to chemotherapy. ImD is characterized by low expression of immune and oncogenic pathways, favorable survival prognosis, low mutation rates of <jats:italic>RUNX1<\/jats:italic> and <jats:italic>TP53<\/jats:italic>, high homeostasis, and low migration potential. ImE exhibits high enrichment of immune and oncogenic pathways, low stemness and proliferation capacity, low homeostasis, high migration potential, and low sensitivity to chemotherapy. Our pathway enrichment-based subtyping approach would offer a promising framework for understanding the molecular heterogeneity of AML and guiding personalized treatment of this disease.<\/jats:p>","DOI":"10.3389\/fphar.2025.1557112","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T07:54:12Z","timestamp":1742543652000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Identifying acute myeloid leukemia subtypes based on pathway enrichment"],"prefix":"10.3389","volume":"16","author":[{"given":"Ling","family":"Zhong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangti","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junze","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4569","DOI":"10.1182\/bloodadvances.2021004583","article-title":"Single-cell polyfunctional proteomics of CD4 cells from patients with AML predicts responses to anti-PD-1-based therapy","volume":"5","author":"Abbas","year":"2021","journal-title":"Blood Adv."},{"key":"B2","unstructured":"VENCLEXTA\u00ae (venetoclax): US prescribing informationNorth Chicago, IL, USA & South San Francisco, CA, USA\n          \n          \n          2020"},{"key":"B3","volume-title":"TIBSOVO\u00ae (ivosidenib)","year":"2018"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2390","DOI":"10.1200\/JCO.2007.13.0096","article-title":"Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the children's oncology group","volume":"26","author":"Aplenc","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.3324\/haematol.2019.220962","article-title":"Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group","volume":"105","author":"Aplenc","year":"2020","journal-title":"Haematologica"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2373","DOI":"10.1182\/blood-2017-09-797712","article-title":"Gemtuzumab ozogamicin for acute myeloid leukemia","volume":"130","author":"Appelbaum","year":"2017","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2391","DOI":"10.1182\/blood-2016-03-643544","article-title":"The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia","volume":"127","author":"Arber","year":"2016","journal-title":"Blood"},{"key":"B8","volume-title":"XOSPATA\u00ae (gilteritinib)","year":"2018"},{"key":"B9","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1111\/j.1365-2141.1976.tb03563.x","article-title":"Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group","volume":"33","author":"Bennett","year":"1976","journal-title":"Br. J. Haematol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1136\/bmj.317.7172.1572","article-title":"Survival probabilities (the Kaplan-Meier method)","volume":"317","author":"Bland","year":"1998","journal-title":"BMJ"},{"key":"B12","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/nm.4439","article-title":"The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions","volume":"24","author":"Bolouri","year":"2018","journal-title":"Nat. Med."},{"key":"B13","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":"B14","unstructured":"IDHIFA\u00ae (enasidenib) tablets: US prescribing information\n          \n          \n          2017"},{"key":"B15","doi-asserted-by":"publisher","first-page":"39098","DOI":"10.18632\/oncotarget.5390","article-title":"An mRNA expression signature for prognostication in de novo acute myeloid leukemia patients with normal karyotype","volume":"6","author":"Chuang","year":"2015","journal-title":"Oncotarget"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2934","DOI":"10.3390\/jcm9092934","article-title":"Targeting PI3K\/Akt\/mTOR in AML: rationale and clinical evidence","volume":"9","author":"Darici","year":"2020","journal-title":"J. Clin. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"127","DOI":"10.3390\/jcm4010127","article-title":"Pediatric AML: from biology to clinical management","volume":"4","author":"de Rooij","year":"2015","journal-title":"J. Clin. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1182\/blood-2016-08-733196","article-title":"Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel","volume":"129","author":"D\u00f6hner","year":"2017","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN","volume":"140","author":"D\u00f6hner","year":"2022","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41571-021-00509-w","article-title":"Towards precision medicine for AML","volume":"18","author":"D\u00f6hner","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B21","first-page":"1136","article-title":"Acute myeloid leukemia","volume":"373","author":"D\u00f6hner","year":"2015"},{"key":"B22","doi-asserted-by":"publisher","first-page":"4589","DOI":"10.1182\/blood-2005-10-4169","article-title":"Role of transforming growth factor-beta in hematologic malignancies","volume":"107","author":"Dong","year":"2006","journal-title":"Blood"},{"key":"B23","doi-asserted-by":"publisher","first-page":"943823","DOI":"10.1155\/2010\/943823","article-title":"Challenges in treating older patients with acute myeloid leukemia","volume":"2010","author":"Eleni","year":"2010","journal-title":"J. Oncol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1200\/JCO.2010.30.5961","article-title":"First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia","volume":"29","author":"Feldman","year":"2011","journal-title":"J. Clin. Oncol. official J. Am. Soc. Clin. Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3021","DOI":"10.1200\/JCO.2014.55.3628","article-title":"Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III children's oncology group trial AAML0531","volume":"32","author":"Gamis","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e008318","DOI":"10.1136\/jitc-2023-008318","article-title":"Paired single-B-cell transcriptomics and receptor sequencing reveal activation states and clonal signatures that characterize B cells in acute myeloid leukemia","volume":"12","author":"Guo","year":"2024","journal-title":"J. Immunother. cancer"},{"key":"B27","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-Seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinforma."},{"key":"B28","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.exphem.2017.07.002","article-title":"Genetic and epigenetic heterogeneity and the impact on cancer relapse","volume":"54","author":"Hassan","year":"2017","journal-title":"Exp. Hematol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1186\/s13046-018-1002-1","article-title":"Classification of triple-negative breast cancers based on Immunogenomic profiling","volume":"37","author":"He","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.annonc.2020.02.018","article-title":"Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Heuser","year":"2020","journal-title":"Ann. Oncol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/s40265-018-1047-7","article-title":"Glasdegib: first global approval","volume":"79","author":"Hoy","year":"2019","journal-title":"Drugs"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th edition of the World Health organization classification of haematolymphoid tumours: myeloid and histiocytic\/dendritic neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"B33","doi-asserted-by":"publisher","first-page":"683","DOI":"10.3390\/biology12050683","article-title":"Understanding the Wnt signaling pathway in acute myeloid leukemia stem cells: a feasible key against relapses","volume":"12","author":"L\u00e1inez-Gonz\u00e1lez","year":"2023","journal-title":"Biology"},{"key":"B34","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinforma."},{"key":"B35","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1007\/s13402-023-00886-7","article-title":"Identifying cancer subtypes based on embryonic and hematopoietic stem cell signatures in pan-cancer","volume":"47","author":"Lei","year":"2024","journal-title":"Cell Oncol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"Ley","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B37","doi-asserted-by":"publisher","first-page":"4472","DOI":"10.1016\/j.csbj.2021.08.005","article-title":"Identification of subtypes correlated with tumor immunity and immunotherapy in cutaneous melanoma","volume":"19","author":"Liu","year":"2021","journal-title":"Comput. Struct. Biotec"},{"key":"B38","doi-asserted-by":"publisher","first-page":"37790","DOI":"10.18632\/oncotarget.26492","article-title":"Precision medicine in the treatment stratification of AML patients: challenges and progress","volume":"9","author":"Lohse","year":"2018","journal-title":"Oncotarget"},{"key":"B39","doi-asserted-by":"publisher","first-page":"bbab260","DOI":"10.1093\/bib\/bbab260","article-title":"oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data","volume":"22","author":"Maeser","year":"2021","journal-title":"Briefings Bioinforma."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: efficient and comprehensive analysis of somatic variants in cancer","volume":"28","author":"Mayakonda","year":"2018","journal-title":"Genome Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"861","DOI":"10.21105\/joss.00861","article-title":"UMAP: uniform manifold approximation and projection","volume":"3","author":"McInnes","year":"2018","journal-title":"J. Open Source Softw."},{"key":"B42","doi-asserted-by":"publisher","first-page":"101073","DOI":"10.1016\/j.blre.2023.101073","article-title":"Advances in NK cell therapy for hematologic malignancies: NK source, persistence and tumor targeting","volume":"60","author":"Merino","year":"2023","journal-title":"Blood Rev."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.3390\/biomedicines9081051","article-title":"The ups and downs of STAT inhibition in acute myeloid leukemia","volume":"9","author":"Moser","year":"2021","journal-title":"Biomedicines"},{"key":"B44","doi-asserted-by":"publisher","first-page":"3974","DOI":"10.3390\/cancers16233974","article-title":"Inflammation and related signaling pathways in acute myeloid leukemia","volume":"16","author":"Naji","year":"2024","journal-title":"Cancers (Basel)"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2907","DOI":"10.3390\/ijms21082907","article-title":"The PI3K-Akt-mTOR signaling pathway in human acute myeloid leukemia (AML) cells","volume":"21","author":"Nepstad","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B46","unstructured":"RYDAPT\u00ae (midostaurin) capsules: US prescribing information\n          \n          \n          2017"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"null","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s13045-022-01228-0","article-title":"Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies","volume":"15","author":"Padella","year":"2022","journal-title":"J. Hematol. & Oncol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2209","DOI":"10.1056\/NEJMoa1516192","article-title":"Genomic classification and prognosis in acute myeloid leukemia","volume":"374","author":"Papaemmanuil","year":"","journal-title":"N. Engl. J. Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2209","DOI":"10.1056\/NEJMoa1516192","article-title":"Genomic classification and prognosis in acute myeloid leukemia","volume":"374","author":"Papaemmanuil","year":"","journal-title":"N. Engl. J. Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1038\/s41375-024-02217-7","article-title":"Targeting the innate immune system in pediatric and adult AML","volume":"38","author":"Perzolli","year":"2024","journal-title":"Leukemia"},{"key":"B52","unstructured":"DaurismoTM (glasdegib) tablets, for oral use: US prescribing information\n          \n          \n          2018"},{"key":"B53","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.cell.2018.03.035","article-title":"Oncogenic signaling pathways in the cancer genome Atlas","volume":"173","author":"Sanchez-Vega","year":"2018","journal-title":"Cell"},{"key":"B54","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1080\/14737140.2019.1652095","article-title":"Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia","volume":"19","author":"Shallis","year":"2019","journal-title":"Expert Rev. Anticancer Ther."},{"key":"B55","doi-asserted-by":"publisher","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"B56","doi-asserted-by":"publisher","first-page":"D607-D613","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B57","doi-asserted-by":"publisher","first-page":"312","DOI":"10.3390\/cells8040312","article-title":"Targeting Hedgehog (hh) pathway for the acute myeloid leukemia treatment","volume":"8","author":"Terao","year":"2019","journal-title":"Cells"},{"key":"B58","doi-asserted-by":"publisher","first-page":"456","DOI":"10.3324\/haematol.2017.178442","article-title":"A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia","volume":"103","author":"Tobias","year":"2018","journal-title":"Haematologica"},{"key":"B59","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s41586-018-0623-z","article-title":"Functional genomic landscape of acute myeloid leukaemia","volume":"562","author":"Tyner","year":"2018","journal-title":"Nature"},{"key":"B60","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1016\/j.cell.2019.01.031","article-title":"Single-cell RNA-seq reveals AML hierarchies relevant to disease progression and immunity","volume":"176","author":"van Galen","year":"2019","journal-title":"Cell"},{"key":"B61","doi-asserted-by":"publisher","first-page":"100634","DOI":"10.1016\/j.blre.2019.100634","article-title":"JAKs to STATs: a tantalizing therapeutic target in acute myeloid leukemia","volume":"40","author":"Venugopal","year":"2020","journal-title":"Blood Rev."},{"key":"B62","doi-asserted-by":"publisher","first-page":"e39731","DOI":"10.1016\/j.heliyon.2024.e39731","article-title":"Immunoediting in acute myeloid leukemia: reappraising T cell exhaustion and the aberrant antigen processing machinery in leukemogenesis","volume":"10","author":"Wang","year":"2024","journal-title":"Heliyon"},{"key":"B63","doi-asserted-by":"publisher","first-page":"975819","DOI":"10.3389\/fped.2022.975819","article-title":"Epigenetic modifications and targeted therapy in pediatric acute myeloid leukemia","volume":"10","author":"Xu","year":"2022","journal-title":"Front. Pediatr."},{"key":"B64","doi-asserted-by":"publisher","first-page":"e35721","DOI":"10.1016\/j.heliyon.2024.e35721","article-title":"Glycolysis and chemoresistance in acute myeloid leukemia","volume":"10","author":"Yang","year":"2024","journal-title":"Heliyon"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1557112\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T07:54:23Z","timestamp":1742543663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1557112\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,21]]},"references-count":64,"alternative-id":["10.3389\/fphar.2025.1557112"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1557112","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,21]]},"article-number":"1557112"}}