{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:03:27Z","timestamp":1788537807216,"version":"build-2803163510"},"reference-count":106,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diseases"],"abstract":"<jats:p>Acute myeloid leukemia (AML) continues to pose significant therapeutic challenges, with high relapse rates driven largely by leukemic stem cells (LSCs), a rare, therapy-resistant population with self-renewal capacity, niche adaptation, and the ability to re-initiate disease. In this state-of-the-art review, we synthesize recent advances in LSC biology, addressing (i) how LSCs differ functionally and phenotypically from normal hematopoietic stem cells (HSCs), (ii) practical approaches for LSC quantification using multiparameter flow cytometry and LSC-enriched marker panels, (iii) the dysregulated signaling, metabolic and epigenetic programs that enable LSC persistence under chemotherapy and contribute to measurable residual disease, and (iv) current therapeutic strategies targeting LSC eradication, including antibody-based therapies, apoptosis and metabolic inhibitors, and emerging epigenetic agents. We also examine the key translational barriers, particularly antigen overlap with normal progenitors, microenvironmental protection, and the need for assay harmonization, while proposing a practical framework for integrating LSC assessment into risk stratification and therapeutic development.<\/jats:p>","DOI":"10.3390\/diseases14020050","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T14:35:46Z","timestamp":1769783746000},"page":"50","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Decoding Leukemic Stem Cells in AML: From Identification to Targeted Eradication"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3432-4209","authenticated-orcid":false,"given":"Elisavet","family":"Apostolidou","sequence":"first","affiliation":[{"name":"Department of Haematology, University Hospital of Ioannina, 45 500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasileios","family":"Georgoulis","sequence":"additional","affiliation":[{"name":"Department of Haematology, University Hospital of Ioannina, 45 500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6649-0491","authenticated-orcid":false,"given":"Dimitrios","family":"Leonardos","sequence":"additional","affiliation":[{"name":"Department of Haematology, University Hospital of Ioannina, 45 500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas","family":"Benetatos","sequence":"additional","affiliation":[{"name":"Department of Haematology, University Hospital of Ioannina, 45 500 Ioannina, Greece"},{"name":"Department of Haematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Kapsali","sequence":"additional","affiliation":[{"name":"Department of Haematology, University Hospital of Ioannina, 45 500 Ioannina, Greece"},{"name":"Department of Haematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4408-5646","authenticated-orcid":false,"given":"Eleftheria","family":"Hatzimichael","sequence":"additional","affiliation":[{"name":"Department of Haematology, University Hospital of Ioannina, 45 500 Ioannina, Greece"},{"name":"Department of Haematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45 500 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3324\/haematol.2022.280800","article-title":"Leukemic stem cells and therapy resistance in acute myeloid leukemia","volume":"108","author":"Stelmach","year":"2023","journal-title":"Haematologica"},{"key":"ref_2","doi-asserted-by":"crossref","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":"Wei","year":"2022","journal-title":"Blood"},{"key":"ref_3","first-page":"46","article-title":"Acute myeloid leukemia management and research in 2025","volume":"75","author":"Kantarjian","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41420-022-01193-0","article-title":"The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting","volume":"8","author":"Chen","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"63","DOI":"10.21037\/atm-23-1824","article-title":"Remodeling of the bone marrow microenvironment during acute myeloid leukemia progression","volume":"12","author":"Urs","year":"2024","journal-title":"Ann. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/367645a0","article-title":"A cell initiating human acute myeloid leukaemia after transplantation into SCID mice","volume":"367","author":"Lapidot","year":"1994","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nm0797-730","article-title":"Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell","volume":"3","author":"Bonnet","year":"1997","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Barreto, I.V., Pessoa, F.M.C.d.P., Machado, C.B., Pantoja, L.d.C., Ribeiro, R.M., Lopes, G.S., Amaral de Moraes, M.E., de Moraes Filho, M.O., de Souza, L.E.B., and Burbano, R.M.R. (2022). Leukemic Stem Cell: A Mini-Review on Clinical Perspectives. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.931050"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.5045\/br.2022.2021221","article-title":"Human acute myeloid leukemia stem cells: Evolution of concept","volume":"57","author":"Shin","year":"2022","journal-title":"Blood Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"344","DOI":"10.20517\/cdr.2021.140","article-title":"Characteristics of leukemic stem cells in acute leukemia and potential targeted therapies for their specific eradication","volume":"5","author":"Hansen","year":"2022","journal-title":"Cancer Drug Resist."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1101\/gad.1143403","article-title":"Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors","volume":"17","author":"Cozzio","year":"2003","journal-title":"Genes. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100962","DOI":"10.1016\/j.xcrm.2023.100962","article-title":"Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells","volume":"4","author":"Mondala","year":"2023","journal-title":"Cell Rep. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Patel, S.B., Nemkov, T., D\u2019Alessandro, A., and Welner, R.S. (2022). Deciphering Metabolic Adaptability of Leukemic Stem Cells. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.846149"},{"key":"ref_14","first-page":"2553","article-title":"Metabolism in stem cell\u2013driven leukemia: Parallels between hematopoiesis and immunity","volume":"141","author":"Rattigan","year":"2023","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.stem.2021.02.013","article-title":"Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors","volume":"28","author":"Jones","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1182\/blood.2022018092","article-title":"Metabolism in acute myeloid leukemia: Mechanistic insights and therapeutic targets","volume":"141","author":"Mishra","year":"2023","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1038\/s41375-025-02645-z","article-title":"Targeting lipid metabolism in acute myeloid leukemia: Biological insights and therapeutic opportunities","volume":"39","author":"Dembitz","year":"2025","journal-title":"Leukemia"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nistic\u00f2, C., and Chiarella, E. (2023). An Overview on Lipid Droplets Accumulation as Novel Target for Acute Myeloid Leukemia Therapy. Biomedicines, 11.","DOI":"10.3390\/biomedicines11123186"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"103753","DOI":"10.1016\/j.critrevonc.2022.103753","article-title":"Theragnostic strategies harnessing the self-renewal pathways of stem-like cells in the acute myeloid leukemia","volume":"177","author":"Bhattacharjee","year":"2022","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12943-016-0574-7","article-title":"Understanding of leukemic stem cells and their clinical implications","volume":"16","author":"Wang","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1182\/blood.2021010980","article-title":"A STAT5B\u2013CD9 axis determines self-renewal in hematopoietic and leukemic stem cells","volume":"138","author":"Kollmann","year":"2021","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhang, H., and Li, S. (2019). Leukemia Stem Cells in the Pathogenesis, Progression, and Treatment of Acute Myeloid Leukemia. Leukemia Stem Cells in Hematologic Malignancies, Springer.","DOI":"10.1007\/978-981-13-7342-8"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.gendis.2023.01.008","article-title":"Signaling pathways governing the behaviors of leukemia stem cells","volume":"11","author":"Azizidoost","year":"2024","journal-title":"Genes Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6314","DOI":"10.1038\/onc.2010.375","article-title":"Hedgehog signaling maintains chemoresistance in myeloid leukemic cells","volume":"29","author":"Queiroz","year":"2010","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/s41467-024-45691-4","article-title":"Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth","volume":"15","author":"Kellaway","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.33696\/Signaling.4.085","article-title":"Augmenting Venetoclax Activity Through Signal Transduction in AML","volume":"4","author":"Bouligny","year":"2023","journal-title":"J. Cell. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Valent, P., Sadovnik, I., Eisenwort, G., Bauer, K., Herrmann, H., Gleixner, K.V., Schulenburg, A., Rabitsch, W., Sperr, W.R., and Wolf, D. (2019). Immunotherapy-Based Targeting and Elimination of Leukemic Stem Cells in AML and CML. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174233"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e180065","DOI":"10.1172\/JCI180065","article-title":"Clonal hematopoiesis and hematological malignancy","volume":"134","author":"Dunn","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Choi, H.-S., Kim, B.S., Yoon, S., Oh, S.-O., and Lee, D. (2024). Leukemic Stem Cells and Hematological Malignancies. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126639"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Marchand, T., and Pinho, S. (2021). Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.775128"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tasian, S.K., Bornh\u00e4user, M., and Rutella, S. (2018). Targeting Leukemia Stem Cells in the Bone Marrow Niche. Biomedicines, 6.","DOI":"10.3390\/biomedicines6010022"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1080\/10428194.2018.1434886","article-title":"Targeting the bone marrow microenvironment in acute leukemia","volume":"59","author":"Karantanou","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Semedo, C., Caro\u00e7o, R., Almeida, A., and Cardoso, B.A. (2024). Targeting the bone marrow niche, moving towards leukemia eradication. Front. Hematol., 3.","DOI":"10.3389\/frhem.2024.1429916"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e10516","DOI":"10.1002\/jbm4.10516","article-title":"From the niche to malignant hematopoiesis and back: Reciprocal interactions between leukemia and the bone marrow microenvironment","volume":"5","author":"Soto","year":"2021","journal-title":"JBMR Plus"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s40164-021-00233-2","article-title":"Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development","volume":"10","author":"Yao","year":"2021","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/leu.2015.252","article-title":"A simple one-tube assay for immunophenotypical quantification of leukemic stem cells in acute myeloid leukemia","volume":"30","author":"Zeijlemaker","year":"2016","journal-title":"Leukemia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/s41375-018-0326-3","article-title":"CD34+CD38\u2212 leukemic stem cell frequency to predict outcome in acute myeloid leukemia","volume":"33","author":"Zeijlemaker","year":"2019","journal-title":"Leukemia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1111\/ijlh.14250","article-title":"Immunophenotypic characterization of leukemic stem cells in acute myeloid leukemia using single tube 10-colour panel by multiparametric flow cytometry: Deciphering the spectrum, complexity and immunophenotypic heterogeneity","volume":"46","author":"Das","year":"2024","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1002\/cyto.b.22201","article-title":"The role of the primitive marker CD133 in CD34-negative acute myeloid leukemia for the detection of leukemia stem cells","volume":"108","author":"Reuvekamp","year":"2025","journal-title":"Cytom. Part B Clin. Cytom."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1002\/cyto.a.24284","article-title":"OMIP 072: A 15-color panel for immunophenotypic identification, quantification, and characterization of leukemic stem cells in children with acute myeloid leukemia","volume":"99","author":"Petersen","year":"2021","journal-title":"Cytom. Part A"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Vergez, F., Nicolau-Travers, M.L., Bertoli, S., Rieu, J.B., Tavitian, S., Bories, P., Luquet, I., Mas, V., Largeaud, L., and Sarry, A. (2020). CD34+CD38\u2212CD123+ Leukemic Stem Cell Frequency Predicts Outcome in Older Acute Myeloid Leukemia Patients Treated by Intensive Chemotherapy but Not Hypomethylating Agents. Cancers, 12.","DOI":"10.3390\/cancers12051174"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e3234","DOI":"10.1002\/hon.3234","article-title":"Tagraxofusp in myeloid malignancies","volume":"42","author":"Bruzzese","year":"2024","journal-title":"Hematol. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1111\/bjh.70019","article-title":"CD123-targeting immunotherapeutic approaches in acute myeloid leukaemia","volume":"207","author":"Dreyzin","year":"2025","journal-title":"Br. J. Haematol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"57811","DOI":"10.18632\/oncotarget.11063","article-title":"Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: Potential impact of BMI-1, TIM-3 and CLL-1","volume":"7","author":"Darwish","year":"2016","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Michelozzi, I.M., Kirtsios, E., and Giustacchini, A. (2021). Driving CAR T Stem Cell Targeting in Acute Myeloid Leukemia: The Roads to Success. Cancers, 13.","DOI":"10.3390\/cancers13112816"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.clml.2021.03.009","article-title":"Leukemic Stem Cell (CD34+\/CD38\u2212\/TIM3+) Frequency in Patients with Acute Myeloid Leukemia: Clinical Implications","volume":"21","author":"Mohamed","year":"2021","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15658","DOI":"10.1038\/s41598-023-42700-2","article-title":"Identification and validation of a prognostic risk-scoring model based on the level of TIM-3 expression in acute myeloid leukemia","volume":"13","author":"Huang","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s12672-025-01797-9","article-title":"Revolutionizing acute myeloid leukemia treatment: A systematic review of immune-based therapies","volume":"16","author":"Ebinama","year":"2025","journal-title":"Discov. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1182\/blood-2017-09-801498","article-title":"Minimal\/measurable residual disease in AML: A consensus document from the European LeukemiaNet MRD Working Party","volume":"131","author":"Schuurhuis","year":"2018","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1182\/blood.2024027408","article-title":"Magrolimab plus azacitidine vs physician\u2019s choice for untreated TP53-mutated acute myeloid leukemia: The ENHANCE-2 study","volume":"146","author":"Zeidner","year":"2025","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"116132","DOI":"10.1016\/j.biopha.2024.116132","article-title":"Immunotherapies of acute myeloid leukemia: Rationale, clinical evidence and perspective","volume":"171","author":"Wu","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1080\/10428194.2017.1410888","article-title":"Expression of multiple leukemic stem cell markers is associated with poor prognosis in de novo acute myeloid leukemia","volume":"59","author":"Yabushita","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2753","DOI":"10.1182\/blood.2021013626","article-title":"2021 Update on MRD in acute myeloid leukemia: A consensus document from the European LeukemiaNet MRD Working Party","volume":"138","author":"Heuser","year":"2021","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Meddi, E., Savi, A., Moretti, F., Mallegni, F., Palmieri, R., Paterno, G., Buzzatti, E., Del Principe, M.I., Buccisano, F., and Venditti, A. (2023). Measurable Residual Disease (MRD) as a Surrogate Efficacy-Response Biomarker in AML. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043062"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Chea, M., Rigolot, L., Canali, A., and Vergez, F. (2024). Minimal Residual Disease in Acute Myeloid Leukemia: Old and New Concepts. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042150"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1111\/ijlh.14348","article-title":"Immunophenotypic features of early haematopoietic and leukaemia stem cells","volume":"46","author":"Reuvekamp","year":"2024","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Cao, S., Wang, Q., and Zhu, G. (2025). From Chemotherapy to Targeted Therapy: Unraveling Resistance in Acute Myeloid Leukemia Through Genetic and Non-Genetic Insights. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094005"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"van Gils, N., Denkers, F., and Smit, L. (2021). Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.659253"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Niu, J., Peng, D., and Liu, L. (2022). Drug Resistance Mechanisms of Acute Myeloid Leukemia Stem Cells. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.896426"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1186\/s13287-021-02659-1","article-title":"Chronic myeloid leukemia stem cells: Targeting therapeutic implications","volume":"12","author":"Mojtahedi","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1158\/1078-0432.CCR-14-2146","article-title":"Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations","volume":"21","author":"Gregory","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1002\/stem.1748","article-title":"The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors","volume":"32","author":"Pellicano","year":"2014","journal-title":"Stem Cells"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nm.4499","article-title":"Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia","volume":"24","author":"Zhang","year":"2018","journal-title":"Nat. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"49451","DOI":"10.18632\/oncotarget.17706","article-title":"Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells","volume":"8","author":"Salati","year":"2017","journal-title":"Oncotarget"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Yung, Y., Lee, E., Chu, H.T., Yip, P.K., and Gill, H. (2021). Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020659"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1053\/j.seminhematol.2008.09.010","article-title":"Leukemia stem cells and human acute lymphoblastic leukemia","volume":"46","author":"Bernt","year":"2009","journal-title":"Semin. Hematol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2919","DOI":"10.1182\/blood-2004-03-0901","article-title":"Characterization of acute lymphoblastic leukemia progenitor cells","volume":"104","author":"Cox","year":"2004","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ccr.2008.05.015","article-title":"In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties","volume":"14","author":"Hotfilder","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/nm1253","article-title":"Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia","volume":"11","author":"Castor","year":"2005","journal-title":"Nat. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5268","DOI":"10.1182\/blood-2010-06-292300","article-title":"Leukemia-initiating cells in human T-lymphoblastic leukemia exhibit glucocorticoid resistance","volume":"116","author":"Chiu","year":"2010","journal-title":"Blood"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.3324\/haematol.2015.138826","article-title":"The myeloma stem cell concept, revisited: From phenomenology to operational terms","volume":"101","author":"Johnsen","year":"2016","journal-title":"Haematologica"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.bbmt.2009.10.024","article-title":"The search for multiple myeloma stem cells: The long and winding road","volume":"16","author":"Basak","year":"2010","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1200\/JCO.2007.15.8428","article-title":"Multiple myeloma cancer stem cells","volume":"26","author":"Huff","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.trecan.2024.06.002","article-title":"Targeting cancer stem cells in multiple myeloma","volume":"10","author":"Gunes","year":"2024","journal-title":"Trends Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1038\/s41375-018-0061-9","article-title":"Mesenchymal stem cells in multiple myeloma: A therapeutical tool or target?","volume":"32","author":"Xu","year":"2018","journal-title":"Leukemia"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Terwijn, M., Zeijlemaker, W., Kelder, A., Rutten, A.P., Snel, A.N., Scholten, W.J., Pabst, T., Verhoef, G., L\u00f6wenberg, B., and Zweegman, S. (2014). Leukemic Stem Cell Frequency: A Strong Biomarker for Clinical Outcome in Acute Myeloid Leukemia. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107587"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1158\/1078-0432.CCR-22-2237","article-title":"Prognostic Impact of Unsupervised Early Assessment of Bulk and Leukemic Stem Cell Measurable Residual Disease in Acute Myeloid Leukemia","volume":"29","author":"Canali","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Kubicka, E., Lum, L.G., Huang, M., and Thakur, A. (2022). Bispecific antibody-targeted T-cell therapy for acute myeloid leukemia. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.899468"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1182\/blood.2020007732","article-title":"Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia","volume":"137","author":"Uy","year":"2021","journal-title":"Blood"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Damiani, D., and Tiribelli, M. (2023). Checkpoint Inhibitors in Acute Myeloid Leukemia. Biomedicines, 11.","DOI":"10.3390\/biomedicines11061724"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.cell.2005.09.025","article-title":"The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis","volume":"123","author":"Yokoyama","year":"2005","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6766","DOI":"10.1038\/sj.onc.1210760","article-title":"Hox genes in hematopoiesis and leukemogenesis","volume":"26","author":"Argiropoulos","year":"2007","journal-title":"Oncogene"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.ccell.2015.02.016","article-title":"Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo","volume":"27","author":"Borkin","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1158\/2159-8290.CD-16-0237","article-title":"Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia","volume":"6","author":"Kuhn","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ccell.2018.08.005","article-title":"Mutant NPM1 Maintains the Leukemic State through HOX Expression","volume":"34","author":"Brunetti","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_86","unstructured":"Food and Drug Administration (2025, December 27). FDA Approves Revumenib for Relapsed or Refractory Acute Leukemia with a KMT2A, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation."},{"key":"ref_87","unstructured":"Food and Drug Administration (2025, December 27). FDA Approves Revumenib for Relapsed or Refractory Acute Myeloid Leukemia with a Susceptible NPM1 Mutation, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-revumenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-npm1-mutation."},{"key":"ref_88","unstructured":"Food and Drug Administration (2025, December 27). FDA Approves Ziftomenib for Relapsed or Refractory Acute Myeloid Leukemia with a NPM1 Mutation, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-ziftomenib-relapsed-or-refractory-acute-myeloid-leukemia-npm1-mutation."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13045-024-01632-8","article-title":"Menin inhibitors for the treatment of acute myeloid leukemia: Challenges and opportunities ahead","volume":"17","author":"Nadiminti","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"104783","DOI":"10.1016\/j.critrevonc.2025.104783","article-title":"Menin Inhibitors in KMT2A-Rearranged and NPM1-Mutated Acute Leukemia: A Scoping Review of Safety and Efficacy","volume":"213","author":"Dali","year":"2025","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"244","DOI":"10.3390\/hematolrep16020024","article-title":"A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia","volume":"16","author":"Candoni","year":"2024","journal-title":"Hematol. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Alexandrova, E., Salvati, A., Pecoraro, G., Lamberti, J., Melone, V., Sellitto, A., Rizzo, F., Giurato, G., Tarallo, R., and Nassa, G. (2022). Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.864612"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1182\/blood-2019-121926","article-title":"A Phase Ib\/II Study of the Histone Methyltransferase Inhibitor Pinometostat in Combination with Azacitidine in Patients with 11q23-Rearranged Acute Myeloid Leukemia","volume":"134","author":"Menghrajani","year":"2019","journal-title":"Blood"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41419-024-06810-7","article-title":"Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia","volume":"15","author":"Nwosu","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Murphy, L.A., and Winters, A.C. (2023). Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells. Biomedicines, 11.","DOI":"10.20944\/preprints202311.1010.v1"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e912","DOI":"10.1097\/HS9.0000000000000912","article-title":"BCL2 Inhibition: A New Paradigm for the Treatment of AML and Beyond","volume":"7","author":"Wei","year":"2023","journal-title":"Hemasphere"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s41392-025-02269-w","article-title":"CAR-T cell therapy for cancer: Current challenges and future directions","volume":"10","author":"Zugasti","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.3324\/haematol.2023.284894","article-title":"Moving forward in target antigen discovery for immunotherapy in acute myeloid leukemia","volume":"109","author":"Buldini","year":"2024","journal-title":"Haematologica"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Barbosa, K., and Deshpande, A.J. (2023). Therapeutic targeting of leukemia stem cells in acute myeloid leukemia. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1204895"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"490","DOI":"10.21147\/j.issn.1000-9604.2025.04.02","article-title":"Strategic innovations: Tackling challenges of immunotherapy in acute myeloid leukemia","volume":"37","author":"Lin","year":"2025","journal-title":"Chin. J. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1038\/nbt1350","article-title":"Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region","volume":"25","author":"Ishikawa","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.stem.2012.12.013","article-title":"BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells","volume":"12","author":"Lagadinou","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Kamel, A.M., Elsharkawy, N.M., Kandeel, E.Z., Hanafi, M., Samra, M., and Osman, R.A. (2022). Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable\/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.867684"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Srinivasan Rajsri, K., Roy, N., and Chakraborty, S. (2023). Acute Myeloid Leukemia Stem Cells in Minimal\/Measurable Residual Disease Detection. Cancers, 15.","DOI":"10.3390\/cancers15102866"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nri2726","article-title":"Awakening dormant haematopoietic stem cells","volume":"10","author":"Trumpp","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nbt.1607","article-title":"Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML","volume":"28","author":"Saito","year":"2010","journal-title":"Nat. Biotechnol."}],"container-title":["Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-9721\/14\/2\/50\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T05:13:14Z","timestamp":1770441194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-9721\/14\/2\/50"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":106,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["diseases14020050"],"URL":"https:\/\/doi.org\/10.3390\/diseases14020050","relation":{},"ISSN":["2079-9721"],"issn-type":[{"value":"2079-9721","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]}}}