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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Chronic myeloid leukaemia (CML), a distinct myeloproliferative neoplasm, results from the malignant reprogramming of haematopoietic stem cells (HSCs) into leukaemia stem cells (LSCs), primarily driven by breakpoint cluster region and Abelson (BCR-ABL1) fusion oncogene. Although the advent of tyrosine kinase inhibitors (TKIs) has significantly transformed clinical management, leading to improved patient survival and quality of life, sustained treatment-free remission (TFR) remains achievable in only a minority of patients. This limitation is largely attributable to the persistence of LSCs and the development of resistance mechanisms. Emerging evidence indicates that LSCs evade TKI-induced apoptosis through aberrant expression of specific cell-surface markers, dysregulated intracellular signalling pathways, and extensive epigenetic alterations. This review examines recent advancements in CML therapy, with a focus on these novel therapeutic targets. It highlights the pivotal role of LSCs in disease progression and relapse, evaluates potential molecular and epigenetic regulators as new targets for intervention, and supports the development of combination treatment strategies to improve TFR rates and move towards curative outcomes.<\/jats:p>","DOI":"10.31083\/fbl48912","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:21:51Z","timestamp":1790698911000},"source":"Crossref","is-referenced-by-count":0,"title":["Recent Advances in Chronic Myeloid Leukaemia (CML): Emerging Molecular and Immunotherapeutic Targets"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7560-5551","authenticated-orcid":true,"given":"Jingyi","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China"},{"name":"Jiangsu Engineering Research Center for Tumor Immunotherapy, 213003 Changzhou, Jiangsu, China"},{"name":"Institute for Cell Therapy of Soochow University, 213003 Changzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4390-3392","authenticated-orcid":true,"given":"Panpan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China"},{"name":"Jiangsu Engineering Research Center for Tumor Immunotherapy, 213003 Changzhou, Jiangsu, China"},{"name":"Institute for Cell Therapy of Soochow University, 213003 Changzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6542-6616","authenticated-orcid":true,"given":"Jian","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China"},{"name":"Jiangsu Engineering Research Center for Tumor Immunotherapy, 213003 Changzhou, Jiangsu, China"},{"name":"Institute for Cell Therapy of Soochow University, 213003 Changzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9316-6387","authenticated-orcid":true,"given":"Linyan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6163-7414","authenticated-orcid":true,"given":"Xiao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China"},{"name":"Jiangsu Engineering Research Center for Tumor Immunotherapy, 213003 Changzhou, Jiangsu, China"},{"name":"Institute for Cell Therapy of Soochow University, 213003 Changzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5410-9242","authenticated-orcid":true,"given":"Lujun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China"},{"name":"Jiangsu Engineering Research Center for Tumor Immunotherapy, 213003 Changzhou, Jiangsu, China"},{"name":"Institute for Cell Therapy of Soochow University, 213003 Changzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3128-9762","authenticated-orcid":true,"given":"Jingting","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China"},{"name":"Jiangsu Engineering Research Center for Tumor Immunotherapy, 213003 Changzhou, Jiangsu, China"},{"name":"Institute for Cell Therapy of Soochow University, 213003 Changzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3277-9998","authenticated-orcid":true,"given":"Zhuojun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Third Affiliated Hospital of Soochow University, 213003 Changzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref1","unstructured":"Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960; 132: 1497. https:\/\/ci.nii.ac.jp\/naid\/10019284064."},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973; 243: 290\u2013293.","DOI":"10.1038\/243290a0"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Heisterkamp N, Stephenson JR, Groffen J, Hansen PF, de Klein A, Bartram CR, et al. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature. 1983; 306: 239\u2013242.","DOI":"10.1038\/306239a0"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Kundu R, Kal N, Singh A, Mukherjee S, Maiti A, Ball S, et al. Epidemiological Trends in Incidence, Death and Associated Risk Factors of Leukemia 1990-2021 and Projection to 2040. Blood. 2024; 144: 1477.","DOI":"10.1182\/blood-2024-211457"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Daltveit DS, Morgan E, Colombet M, Steliarova-Foucher E, Bendahhou K, Marcos-Gragera R, et al. Global patterns of leukemia by subtype, age, and sex in 185 countries in 2022. Leukemia. 2025; 39: 412\u2013419.","DOI":"10.1038\/s41375-024-02452-y"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Yun Z, Zhang Y, Wang J, Xue C, Wu J, Han X, et al. Global, Regional and National Burden of Leukemia, 1990-2021: Analysis of Data from the Global Burden of Disease Study 2021. Blood. 2024; 144: 7907.","DOI":"10.1182\/blood-2024-205478"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Chen J, Pang W, Deng M, Zheng R, Chen Y, Zhang Z, et al. Global, regional, and national burden of leukemia, 1990-2021: a systematic analysis of the global burden of disease in 2021. Frontiers in Medicine. 2025; 12: 1542317.","DOI":"10.3389\/fmed.2025.1542317"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Wiedmeier-Nutor J, Leis J. Chronic Lymphocytic Leukemia: Chemotherapy Free and Other Novel Therapies Including CAR T. Current Treatment Options in Oncology. 2022; 23: 904\u2013919.","DOI":"10.1007\/s11864-022-00953-5"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Goldberg SL, Savona M, Mauro MJ. Considerations for Successful Treatment-free Remission in Chronic Myeloid Leukemia. Clinical Lymphoma, Myeloma & Leukemia. 2018; 18: 98\u2013105.","DOI":"10.1016\/j.clml.2017.11.006"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. The Lancet. Oncology. 2018; 19: 747\u2013757.","DOI":"10.1016\/S1470-2045(18)30192-X"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Molica M, Noguera NI, Trawinska MM, Martinelli G, Cerchione C, Abruzzese E. Treatment free remission in chronic myeloid leukemia: Lights and shadows. Hematology Reports. 2020; 12: 8950.","DOI":"10.4081\/hr.2020.8950"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Pavlovsky C, Abello Polo V, Pagnano K, Varela AI, Agudelo C, Bianchini M, et al. Treatment-free remission in patients with chronic myeloid leukemia: recommendations of the LALNET expert panel. Blood Advances. 2021; 5: 4855\u20134863.","DOI":"10.1182\/bloodadvances.2020003235"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Bourne G, Bhatia R, Jamy O. Treatment-Free Remission in Chronic Myeloid Leukemia. Journal of Clinical Medicine. 2024; 13: 2567.","DOI":"10.3390\/jcm13092567"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Punatar S, Jindal N, Gokarn A, Mirgh S, Chichra A, Nayak L, et al. Treatment free remission (TFR) in chronic myeloid leukemia-results, compliance and patterns of failure from a tertiary care cancer centre in India. Blood Cancer Journal. 2025; 15: 186.","DOI":"10.1038\/s41408-025-01390-x"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367: 645\u2013648.","DOI":"10.1038\/367645a0"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood. 2017; 129: 1595\u20131606.","DOI":"10.1182\/blood-2016-09-696013"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Herrmann H, Sadovnik I, Cerny-Reiterer S, R\u00fclicke T, Stefanzl G, Willmann M, et al. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood. 2014; 123: 3951\u20133962.","DOI":"10.1182\/blood-2013-10-536078"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Herrmann H, Sadovnik I, Eisenwort G, R\u00fclicke T, Blatt K, Herndlhofer S, et al. Delineation of target expression profiles in CD34+\/CD38- and CD34+\/CD38+ stem and progenitor cells in AML and CML. Blood Advances. 2020; 4: 5118\u20135132.","DOI":"10.1182\/bloodadvances.2020001742"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S, et al. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. 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CD34(+)\/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab\/ozogamicin. Haematologica. 2012; 97: 219\u2013226.","DOI":"10.3324\/haematol.2010.035006"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Ehninger A, Kramer M, R\u00f6llig C, Thiede C, Bornh\u00e4user M, von Bonin M, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer Journal. 2014; 4: e218.","DOI":"10.1038\/bcj.2014.39"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Zeijlemaker W, Kelder A, Oussoren-Brockhoff YJM, Scholten WJ, Snel AN, Veldhuizen D, et al. A simple one-tube assay for immunophenotypical quantification of leukemic stem cells in acute myeloid leukemia. Leukemia. 2016; 30: 439\u2013446.","DOI":"10.1038\/leu.2015.252"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH. Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. Journal of Immunology. 1984; 133: 157\u2013165.","DOI":"10.4049\/jimmunol.133.1.157"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Furness SGB, McNagny K. Beyond mere markers: functions for CD34 family of sialomucins in hematopoiesis. Immunologic Research. 2006; 34: 13\u201332.","DOI":"10.1385\/IR:34:1:13"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Jiang Z, Wu D, Lin S, Li P. CD34 and CD38 are prognostic biomarkers for acute B lymphoblastic leukemia. Biomarker Research. 2016; 4: 23.","DOI":"10.1186\/s40364-016-0080-5"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"Deaglio S, Mehta K, Malavasi F. Human CD38: a (r)evolutionary story of enzymes and receptors. Leukemia Research. 2001; 25: 1\u201312.","DOI":"10.1016\/s0145-2126(00)00093-x"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"Li Y, Zhong G, Sun W, Zhao C, Zhang P, Song J, et al. CD44 deficiency inhibits unloading-induced cortical bone loss through downregulation of osteoclast activity. Scientific Reports. 2015; 5: 16124.","DOI":"10.1038\/srep16124"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Karousou E, Misra S, Ghatak S, Dobra K, G\u00f6tte M, Vigetti D, et al. Roles and targeting of the HAS\/hyaluronan\/CD44 molecular system in cancer. Matrix Biology. 2017; 59: 3\u201322.","DOI":"10.1016\/j.matbio.2016.10.001"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Senbanjo LT, Chellaiah MA. CD44: A Multifunctional Cell Surface Adhesion Receptor Is a Regulator of Progression and Metastasis of Cancer Cells. 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Biomolecules. 2021; 11: 1850.","DOI":"10.3390\/biom11121850"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Shi R, Liu X. CD44: a potential therapeutic target in chronic myeloid leukemia. Die Pharmazie. 2021; 76: 574\u2013578.","DOI":"10.1691\/ph.2021.1744"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"van Rhenen A, Moshaver B, Kelder A, Feller N, Nieuwint AWM, Zweegman S, et al. Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. Leukemia. 2007; 21: 1700\u20131707.","DOI":"10.1038\/sj.leu.2404754"},{"key":"ref37","doi-asserted-by":"publisher","unstructured":"Frolova O, Benito J, Brooks C, Wang RY, Korchin B, Rowinsky EK, et al. SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia. British Journal of Haematology. 2014; 166: 862\u2013874.","DOI":"10.1111\/bjh.12978"},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"Han L, Jorgensen JL, Brooks C, Shi C, Zhang Q, Nogueras Gonz\u00e1lez GM, et al. Antileukemia Efficacy and Mechanisms of Action of SL-101, a Novel Anti-CD123 Antibody Conjugate, in Acute Myeloid Leukemia. Clinical Cancer Research. 2017; 23: 3385\u20133395.","DOI":"10.1158\/1078-0432.CCR-16-1904"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"Wittwer NL, Brumatti G, Marchant C, Sandow JJ, Pudney MK, Dottore M, et al. High CD123 levels enhance proliferation in response to IL-3, but reduce chemotaxis by downregulating CXCR4 expression. Blood Advances. 2017; 1: 1067\u20131079.","DOI":"10.1182\/bloodadvances.2016002931"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"El Achi H, Dupont E, Paul S, Khoury JD. CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies. Cancers. 2020; 12: 3087.","DOI":"10.3390\/cancers12113087"},{"key":"ref41","doi-asserted-by":"publisher","unstructured":"J\u00e4r\u00e5s M, Johnels P, Hansen N, Agerstam H, Tsapogas P, Rissler M, et al. Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107: 16280\u201316285.","DOI":"10.1073\/pnas.1004408107"},{"key":"ref42","doi-asserted-by":"publisher","unstructured":"Barreyro L, Will B, Bartholdy B, Zhou L, Todorova TI, Stanley RF, et al. Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood. 2012; 120: 1290\u20131298.","DOI":"10.1182\/blood-2012-01-404699"},{"key":"ref43","doi-asserted-by":"publisher","unstructured":"Askmyr M, \u00c5gerstam H, Hansen N, Gordon S, Arvanitakis A, Rissler M, et al. Selective killing of candidate AML stem cells by antibody targeting of IL1RAP. Blood. 2013; 121: 3709\u20133713.","DOI":"10.1182\/blood-2012-09-458935"},{"key":"ref44","doi-asserted-by":"publisher","unstructured":"\u00c5gerstam H, Karlsson C, Hansen N, Sand\u00e9n C, Askmyr M, von Palffy S, et al. Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America. 2015; 112: 10786\u201310791.","DOI":"10.1073\/pnas.1422749112"},{"key":"ref45","doi-asserted-by":"publisher","unstructured":"\u00c5gerstam H, Hansen N, von Palffy S, Sand\u00e9n C, Reckzeh K, Karlsson C, et al. IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models. Blood. 2016; 128: 2683\u20132693.","DOI":"10.1182\/blood-2015-11-679985"},{"key":"ref46","doi-asserted-by":"publisher","unstructured":"Park KW, Morrison CM, Sorensen LK, Jones CA, Rao Y, Chien CB, et al. Robo4 is a vascular-specific receptor that inhibits endothelial migration. Developmental Biology. 2003; 261: 251\u2013267.","DOI":"10.1016\/s0012-1606(03)00258-6"},{"key":"ref47","doi-asserted-by":"publisher","unstructured":"Shibata F, Goto-Koshino Y, Morikawa Y, Komori T, Ito M, Fukuchi Y, et al. Roundabout 4 is expressed on hematopoietic stem cells and potentially involved in the niche-mediated regulation of the side population phenotype. Stem Cells. 2009; 27: 183\u2013190.","DOI":"10.1634\/stemcells.2008-0292"},{"key":"ref48","doi-asserted-by":"publisher","unstructured":"Smith-Berdan S, Nguyen A, Hassanein D, Zimmer M, Ugarte F, Ciriza J, et al. Robo4 cooperates with CXCR4 to specify hematopoietic stem cell localization to bone marrow niches. Cell Stem Cell. 2011; 8: 72\u201383.","DOI":"10.1016\/j.stem.2010.11.030"},{"key":"ref49","doi-asserted-by":"publisher","unstructured":"Raspadori D, Pacelli P, Sicuranza A, Abruzzese E, Iurlo A, Cattaneo D, et al. Flow Cytometry Assessment of CD26+ Leukemic Stem Cells in Peripheral Blood: A Simple and Rapid New Diagnostic Tool for Chronic Myeloid Leukemia. Cytometry. Part B, Clinical Cytometry. 2019; 96: 294\u2013299.","DOI":"10.1002\/cyto.b.21764"},{"key":"ref50","doi-asserted-by":"publisher","unstructured":"Sicuranza A, Cavalleri A, Bernardi S. The biology of chronic myeloid leukemia: an overview of the new insights and biomarkers. Frontiers in Oncology. 2025; 15: 1546813.","DOI":"10.3389\/fonc.2025.1546813"},{"key":"ref51","doi-asserted-by":"publisher","unstructured":"Bocchia M, Sicuranza A, Abruzzese E, Iurlo A, Sirianni S, Gozzini A, et al. Residual Peripheral Blood CD26+ Leukemic Stem Cells in Chronic Myeloid Leukemia Patients During TKI Therapy and During Treatment-Free Remission. Frontiers in Oncology. 2018; 8: 194.","DOI":"10.3389\/fonc.2018.00194"},{"key":"ref52","doi-asserted-by":"publisher","unstructured":"Bocchia M, Sicuranza A, Pacelli P, Iurlo A, Abruzzese E, Galimberti S, et al. Peripheral Blood CD26+ Leukemia Stem Cells Monitoring in Chronic Myeloid Leukemia Patients from Diagnosis to Response to TKIs: Interim Results of a Multicenter Prospective Study (PROSPECTIVE FLOWERS). Blood. 2020; 136: 45\u201346.","DOI":"10.1182\/blood-2020-139306"},{"key":"ref53","doi-asserted-by":"publisher","unstructured":"Soverini S, De Santis S, Monaldi C, Bruno S, Mancini M. Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort? International Journal of Molecular Sciences. 2021; 22: 7093.","DOI":"10.3390\/ijms22137093"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Landberg N, Hansen N, Askmyr M, \u00c5gerstam H, Lassen C, Rissler M, et al. IL1RAP expression as a measure of leukemic stem cell burden at diagnosis of chronic myeloid leukemia predicts therapy outcome. 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Experimental Hematology. 2018; 57: 50\u201359.e6.","DOI":"10.1016\/j.exphem.2017.09.012"},{"key":"ref57","doi-asserted-by":"publisher","unstructured":"Ruiz MS, S\u00e1nchez MB, Bonecker S, Furtado C, Koile D, Yankilevich P, et al. miRNome profiling of LSC-enriched CD34+CD38\u2013CD26+ fraction in Ph+ CML-CP samples from Argentinean patients: a potential new pharmacogenomic tool. Frontiers in Pharmacology. 2021; 11: 612573.","DOI":"10.3389\/fphar.2020.612573"},{"key":"ref58","doi-asserted-by":"publisher","unstructured":"Houshmand M, Garello F, Stefania R, Gaidano V, Cignetti A, Spinelli M, et al. Targeting Chronic Myeloid Leukemia Stem\/Progenitor Cells Using Venetoclax-Loaded Immunoliposome. Cancers. 2021; 13: 1311.","DOI":"10.3390\/cancers13061311"},{"key":"ref59","doi-asserted-by":"publisher","unstructured":"Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009; 458: 776\u2013779.","DOI":"10.1038\/nature07737"},{"key":"ref60","doi-asserted-by":"publisher","unstructured":"Long B, Zhu H, Zhu C, Liu T, Meng W. Activation of the Hedgehog pathway in chronic myelogeneous leukemia patients. Journal of Experimental & Clinical Cancer Research. 2011; 30: 8.","DOI":"10.1186\/1756-9966-30-8"},{"key":"ref61","doi-asserted-by":"publisher","unstructured":"Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008; 14: 238\u2013249.","DOI":"10.1016\/j.ccr.2008.08.003"},{"key":"ref62","doi-asserted-by":"publisher","unstructured":"Chen Y, Peng C, Sullivan C, Li D, Li S. Critical molecular pathways in cancer stem cells of chronic myeloid leukemia. Leukemia. 2010; 24: 1545\u20131554.","DOI":"10.1038\/leu.2010.143"},{"key":"ref63","doi-asserted-by":"publisher","unstructured":"Su W, Meng F, Huang L, Zheng M, Liu W, Sun H. Sonic hedgehog maintains survival and growth of chronic myeloid leukemia progenitor cells through \u03b2-catenin signaling. Experimental Hematology. 2012; 40: 418\u2013427.","DOI":"10.1016\/j.exphem.2012.01.003"},{"key":"ref64","doi-asserted-by":"publisher","unstructured":"Niewiadomski P, Niedzi\u00f3\u0142ka SM, Markiewicz \u0141, U\u015bpie\u0144ski T, Baran B, Chojnowska K. Gli Proteins: Regulation in Development and Cancer. Cells. 2019; 8: 147.","DOI":"10.3390\/cells8020147"},{"key":"ref65","doi-asserted-by":"publisher","unstructured":"Sicurella M, De Chiara M, Neri LM. Hedgehog and PI3K\/Akt\/mTOR Signaling Pathways Involvement in Leukemic Malignancies: Crosstalk and Role in Cell Death. Cells. 2025; 14: 269.","DOI":"10.3390\/cells14040269"},{"key":"ref66","doi-asserted-by":"publisher","unstructured":"Yang D, Cao F, Ye X, Zhao H, Liu X, Li Y, et al. Arsenic trioxide inhibits the Hedgehog pathway which is aberrantly activated in acute promyelocytic leukemia. Acta Haematologica. 2013; 130: 260\u2013267.","DOI":"10.1159\/000351603"},{"key":"ref67","doi-asserted-by":"publisher","unstructured":"Heidel FH, Arreba-Tutusaus P, Armstrong SA, Fischer T. Evolutionarily conserved signaling pathways: acting in the shadows of acute myelogenous leukemia\u2019s genetic diversity. Clinical Cancer Research. 2015; 21: 240\u2013248.","DOI":"10.1158\/1078-0432.CCR-14-1436"},{"key":"ref68","doi-asserted-by":"publisher","unstructured":"Jamieson C, Martinelli G, Papayannidis C, Cortes JE. Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia. Blood Cancer Discovery. 2020; 1: 134\u2013145.","DOI":"10.1158\/2643-3230.BCD-20-0007"},{"key":"ref69","doi-asserted-by":"publisher","unstructured":"Khaldoyanidi SK, Hindoyan A, Stein A, Subklewe M. Leukemic stem cells as a target for eliminating acute myeloid leukemia: Gaps in translational research. Critical Reviews in Oncology\/Hematology. 2022; 175: 103710.","DOI":"10.1016\/j.critrevonc.2022.103710"},{"key":"ref70","doi-asserted-by":"publisher","unstructured":"Fukushima N, Minami Y, Kakiuchi S, Kuwatsuka Y, Hayakawa F, Jamieson C, et al. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Science. 2016; 107: 1422\u20131429.","DOI":"10.1111\/cas.13019"},{"key":"ref71","doi-asserted-by":"publisher","unstructured":"Lainez-Gonz\u00e1lez D, Serrano-L\u00f3pez J, Alonso-Dom\u00ednguez JM. Understanding the Hedgehog Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Necessary Step toward a Cure. Biology. 2021; 10: 255.","DOI":"10.3390\/biology10040255"},{"key":"ref72","doi-asserted-by":"publisher","unstructured":"Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics. 2009; 41: 783\u2013792.","DOI":"10.1038\/ng.389"},{"key":"ref73","doi-asserted-by":"publisher","unstructured":"Lucas CM, Harris RJ, Giannoudis A, McDonald E, Clark RE. Low leukotriene B4 receptor 1 leads to ALOX5 downregulation at diagnosis of chronic myeloid leukemia. Haematologica. 2014; 99: 1710\u20131715.","DOI":"10.3324\/haematol.2013.101972"},{"key":"ref74","doi-asserted-by":"publisher","unstructured":"Bijlsma MF, Borensztajn KS, Roelink H, Peppelenbosch MP, Spek CA. Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites. Cellular Signalling. 2007; 19: 2596\u20132604.","DOI":"10.1016\/j.cellsig.2007.08.011"},{"key":"ref75","doi-asserted-by":"publisher","unstructured":"Niu J, Peng D, Liu L. Drug Resistance Mechanisms of Acute Myeloid Leukemia Stem Cells. Frontiers in Oncology. 2022; 12: 896426.","DOI":"10.3389\/fonc.2022.896426"},{"key":"ref76","doi-asserted-by":"publisher","unstructured":"Irvine DA, Zhang B, Allan EK, Holyoake TL, Dorsch M, Manley PW, et al. Combination of the Hedgehog Pathway Inhibitor LDE225 and Nilotinib Eliminates Chronic Myeloid Leukemia Stem and Progenitor Cells. Blood. 2009; 114: 1428.","DOI":"10.1182\/blood.V114.22.1428.1428"},{"key":"ref77","doi-asserted-by":"publisher","unstructured":"Zhang B, Irvine D, Ho YW, Buonamici S, Manley P, Holyoake TL, et al. Inhibition of Chronic Myeloid Leukemia Stem Cells by the Combination of the Hedgehog Pathway Inhibitor LDE225 with Nilotinib. Blood. 2010; 116: 514.","DOI":"10.1182\/blood.V116.21.514.514"},{"key":"ref78","doi-asserted-by":"publisher","unstructured":"Turner KA, Chen M, Rothe K, Forrest DL, Jiang X. Dual Targeting of Smoothened, a Key Regulator in the Hedgehog Pathway, and BCR-ABL1 Effectively Eradicates Drug-Insensitive Stem\/Progenitor Cells in Chronic Myeloid Leukemia. Cells. 2025; 14: 1565.","DOI":"10.3390\/cells14191565"},{"key":"ref79","doi-asserted-by":"publisher","unstructured":"Weng AP, Ferrando AA, Lee W, Morris IV JP, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004; 306: 269\u2013271.","DOI":"10.1126\/science.1102160"},{"key":"ref80","doi-asserted-by":"publisher","unstructured":"Zhou HM, Zhang JG, Zhang X, Li Q. Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents. Signal Transduction and Targeted Therapy. 2021; 6: 62.","DOI":"10.1038\/s41392-020-00430-1"},{"key":"ref81","doi-asserted-by":"publisher","unstructured":"Duncan AW, Rattis FM, DiMascio LN, Congdon KL, Pazianos G, Zhao C, et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nature Immunology. 2005; 6: 314\u2013322.","DOI":"10.1038\/ni1164"},{"key":"ref82","doi-asserted-by":"publisher","unstructured":"Rosati E, Sabatini R, Rampino G, Tabilio A, Di Ianni M, Fettucciari K, et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood. 2009; 113: 856\u2013865.","DOI":"10.1182\/blood-2008-02-139725"},{"key":"ref83","doi-asserted-by":"publisher","unstructured":"Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Zhu N, et al. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. The Journal of Experimental Medicine. 2013; 210: 301\u2013319.","DOI":"10.1084\/jem.20121484"},{"key":"ref84","doi-asserted-by":"publisher","unstructured":"Chiang MY, Shestova O, Xu L, Aster JC, Pear WS. Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells. Blood. 2013; 121: 905\u2013917.","DOI":"10.1182\/blood-2012-03-416503"},{"key":"ref85","doi-asserted-by":"publisher","unstructured":"Moradi F, Babashah S, Sadeghizadeh M, Jalili A, Hajifathali A, Roshandel H. Signaling pathways involved in chronic myeloid leukemia pathogenesis: The importance of targeting Musashi2-Numb signaling to eradicate leukemia stem cells. Iranian Journal of Basic Medical Sciences. 2019; 22: 581\u2013589.","DOI":"10.22038\/ijbms.2019.31879.7666"},{"key":"ref86","doi-asserted-by":"publisher","unstructured":"Nakahara F, Sakata-Yanagimoto M, Komeno Y, Kato N, Uchida T, Haraguchi K, et al. Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. Blood. 2010; 115: 2872\u20132881.","DOI":"10.1182\/blood-2009-05-222836"},{"key":"ref87","doi-asserted-by":"publisher","unstructured":"Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt\/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010; 327: 1650\u20131653.","DOI":"10.1126\/science.1186624"},{"key":"ref88","doi-asserted-by":"publisher","unstructured":"MacDonald BT, Tamai K, He X. Wnt\/beta-catenin signaling: components, mechanisms, and diseases. Developmental Cell. 2009; 17: 9\u201326.","DOI":"10.1016\/j.devcel.2009.06.016"},{"key":"ref89","doi-asserted-by":"publisher","unstructured":"Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003; 423: 409\u2013414.","DOI":"10.1038\/nature01593"},{"key":"ref90","doi-asserted-by":"publisher","unstructured":"Lim S, Saw TY, Zhang M, Janes MR, Nacro K, Hill J, et al. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proceedings of the National Academy of Sciences of the United States of America. 2013; 110: E2298\u2013E2307.","DOI":"10.1073\/pnas.1301838110"},{"key":"ref91","doi-asserted-by":"publisher","unstructured":"Agarwal P, Zhang B, Ho Y, Cook A, Li L, Mikhail FM, et al. Enhanced targeting of CML stem and progenitor cells by inhibition of porcupine acyltransferase in combination with TKI. Blood. 2017; 129: 1008\u20131020.","DOI":"10.1182\/blood-2016-05-714089"},{"key":"ref92","doi-asserted-by":"publisher","unstructured":"Grassi S, Palumbo S, Mariotti V, Liberati D, Guerrini F, Ciabatti E, et al. The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia. Frontiers in Oncology. 2019; 9: 532.","DOI":"10.3389\/fonc.2019.00532"},{"key":"ref93","doi-asserted-by":"publisher","unstructured":"Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt\/\u03b2-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduction and Targeted Therapy. 2022; 7: 3.","DOI":"10.1038\/s41392-021-00762-6"},{"key":"ref94","doi-asserted-by":"publisher","unstructured":"Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-\u03b2-catenin signaling. Blood. 2013; 121: 1824\u20131838.","DOI":"10.1182\/blood-2012-02-412890"},{"key":"ref95","doi-asserted-by":"publisher","unstructured":"Abrahamsson AE, Geron I, Gotlib J, Dao KHT, Barroga CF, Newton IG, et al. Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proceedings of the National Academy of Sciences of the United States of America. 2009; 106: 3925\u20133929.","DOI":"10.1073\/pnas.0900189106"},{"key":"ref96","doi-asserted-by":"publisher","unstructured":"Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. The New England Journal of Medicine. 2004; 351: 657\u2013667.","DOI":"10.1056\/NEJMoa040258"},{"key":"ref97","doi-asserted-by":"publisher","unstructured":"Herr P, Basler K. Porcupine-mediated lipidation is required for Wnt recognition by Wls. Developmental Biology. 2012; 361: 392\u2013402.","DOI":"10.1016\/j.ydbio.2011.11.003"},{"key":"ref98","doi-asserted-by":"publisher","unstructured":"Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proceedings of the National Academy of Sciences of the United States of America. 2013; 110: 20224\u201320229.","DOI":"10.1073\/pnas.1314239110"},{"key":"ref99","doi-asserted-by":"publisher","unstructured":"Zhao X, Shao P, Gai K, Li F, Shan Q, Xue HH. \u03b2-catenin and \u03b3-catenin are dispensable for T lymphocytes and AML leukemic stem cells. eLife. 2020; 9: e55360.","DOI":"10.7554\/eLife.55360"},{"key":"ref100","doi-asserted-by":"publisher","unstructured":"Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nature Reviews. Clinical Oncology. 2015; 12: 445\u2013464.","DOI":"10.1038\/nrclinonc.2015.61"},{"key":"ref101","doi-asserted-by":"publisher","unstructured":"Acar A, Hidalgo-Sastre A, Leverentz MK, Mills CG, Woodcock S, Baron M, et al. Inhibition of Wnt signalling by Notch via two distinct mechanisms. Scientific Reports. 2021; 11: 9096.","DOI":"10.1038\/s41598-021-88618-5"},{"key":"ref102","doi-asserted-by":"publisher","unstructured":"Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010; 463: 676\u2013680.","DOI":"10.1038\/nature08734"},{"key":"ref103","doi-asserted-by":"publisher","unstructured":"Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS, et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science. 1993; 262: 747\u2013750.","DOI":"10.1126\/science.8235596"},{"key":"ref104","doi-asserted-by":"publisher","unstructured":"Wong CW, Privalsky ML. Transcriptional repression by the SMRT-mSin3 corepressor: multiple interactions, multiple mechanisms, and a potential role for TFIIB. Molecular and Cellular Biology. 1998; 18: 5500\u20135510.","DOI":"10.1128\/MCB.18.9.5500"},{"key":"ref105","doi-asserted-by":"publisher","unstructured":"Lemercier C, Brocard MP, Puvion-Dutilleul F, Kao HY, Albagli O, Khochbin S. Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor. The Journal of Biological Chemistry. 2002; 277: 22045\u201322052.","DOI":"10.1074\/jbc.M201736200"},{"key":"ref106","doi-asserted-by":"publisher","unstructured":"Cattoretti G, Pasqualucci L, Ballon G, Tam W, Nandula SV, Shen Q, et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell. 2005; 7: 445\u2013455.","DOI":"10.1016\/j.ccr.2005.03.037"},{"key":"ref107","doi-asserted-by":"publisher","unstructured":"Ranuncolo SM, Wang L, Polo JM, Dell\u2019Oso T, Dierov J, Gaymes TJ, et al. BCL6-mediated attenuation of DNA damage sensing triggers growth arrest and senescence through a p53-dependent pathway in a cell context-dependent manner. The Journal of Biological Chemistry. 2008; 283: 22565\u201322572.","DOI":"10.1074\/jbc.M803490200"},{"key":"ref108","doi-asserted-by":"publisher","unstructured":"Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science. 1997; 276: 589\u2013592.","DOI":"10.1126\/science.276.5312.589"},{"key":"ref109","doi-asserted-by":"publisher","unstructured":"Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R, et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nature Genetics. 1997; 16: 161\u2013170.","DOI":"10.1038\/ng0697-161"},{"key":"ref110","doi-asserted-by":"publisher","unstructured":"Ichii H, Sakamoto A, Kuroda Y, Tokuhisa T. Bcl6 acts as an amplifier for the generation and proliferative capacity of central memory CD8+ T cells. Journal of Immunology. 2004; 173: 883\u2013891.","DOI":"10.4049\/jimmunol.173.2.883"},{"key":"ref111","doi-asserted-by":"publisher","unstructured":"Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature. 2004; 432: 635\u2013639.","DOI":"10.1038\/nature03147"},{"key":"ref112","doi-asserted-by":"publisher","unstructured":"Ichii H, Sakamoto A, Arima M, Hatano M, Kuroda Y, Tokuhisa T. Bcl6 is essential for the generation of long-term memory CD4+ T cells. International Immunology. 2007; 19: 427\u2013433.","DOI":"10.1093\/intimm\/dxm007"},{"key":"ref113","doi-asserted-by":"publisher","unstructured":"Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009; 325: 1001\u20131005.","DOI":"10.1126\/science.1176676"},{"key":"ref114","doi-asserted-by":"publisher","unstructured":"Duy C, Yu JJ, Nahar R, Swaminathan S, Kweon SM, Polo JM, et al. BCL6 is critical for the development of a diverse primary B cell repertoire. The Journal of Experimental Medicine. 2010; 207: 1209\u20131221.","DOI":"10.1084\/jem.20091299"},{"key":"ref115","doi-asserted-by":"publisher","unstructured":"Hatzi K, Nance JP, Kroenke MA, Bothwell M, Haddad EK, Melnick A, et al. BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. The Journal of Experimental Medicine. 2015; 212: 539\u2013553.","DOI":"10.1084\/jem.20141380"},{"key":"ref116","doi-asserted-by":"publisher","unstructured":"Choi J, Crotty S. Bcl6-Mediated Transcriptional Regulation of Follicular Helper T cells (TFH). Trends in Immunology. 2021; 42: 336\u2013349.","DOI":"10.1016\/j.it.2021.02.002"},{"key":"ref117","doi-asserted-by":"publisher","unstructured":"Walker SR, Nelson EA, Frank DA. STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene. 2007; 26: 224\u2013233.","DOI":"10.1038\/sj.onc.1209775"},{"key":"ref118","doi-asserted-by":"publisher","unstructured":"Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, et al. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. The Journal of Experimental Medicine. 2011; 208: 2163\u20132174.","DOI":"10.1084\/jem.20110304"},{"key":"ref119","doi-asserted-by":"publisher","unstructured":"Cerchietti LC, Yang SN, Shaknovich R, Hatzi K, Polo JM, Chadburn A, et al. A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo. Blood. 2009; 113: 3397\u20133405.","DOI":"10.1182\/blood-2008-07-168773"},{"key":"ref120","doi-asserted-by":"publisher","unstructured":"Cerchietti LC, Ghetu AF, Zhu X, Da Silva GF, Zhong S, Matthews M, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell. 2010; 17: 400\u2013411.","DOI":"10.1016\/j.ccr.2009.12.050"},{"key":"ref121","doi-asserted-by":"publisher","unstructured":"Madapura HS, Nagy N, Ujvari D, Kallas T, Kr\u00f6hnke MCL, Amu S, et al. Interferon \u03b3 is a STAT1-dependent direct inducer of BCL6 expression in imatinib-treated chronic myeloid leukemia cells. Oncogene. 2017; 36: 4619\u20134628.","DOI":"10.1038\/onc.2017.85"},{"key":"ref122","doi-asserted-by":"publisher","unstructured":"Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011; 469: 343\u2013349.","DOI":"10.1038\/nature09784"},{"key":"ref123","doi-asserted-by":"publisher","unstructured":"B\u00e9guelin W, Teater M, Gearhart MD, Calvo Fern\u00e1ndez MT, Goldstein RL, C\u00e1rdenas MG, et al. EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis. Cancer Cell. 2016; 30: 197\u2013213.","DOI":"10.1016\/j.ccell.2016.07.006"},{"key":"ref124","doi-asserted-by":"publisher","unstructured":"Mochizuki-Kashio M, Mishima Y, Miyagi S, Negishi M, Saraya A, Konuma T, et al. Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood. 2011; 118: 6553\u20136561.","DOI":"10.1182\/blood-2011-03-340554"},{"key":"ref125","doi-asserted-by":"publisher","unstructured":"Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-\u03b2-catenin signaling. Cancer Cell. 2011; 19: 86\u2013100.","DOI":"10.1016\/j.ccr.2010.10.035"},{"key":"ref126","doi-asserted-by":"publisher","unstructured":"Shi J, Wang E, Zuber J, Rappaport A, Taylor M, Johns C, et al. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9; Nras(G12D) acute myeloid leukemia. Oncogene. 2013; 32: 930\u2013938.","DOI":"10.1038\/onc.2012.110"},{"key":"ref127","doi-asserted-by":"publisher","unstructured":"Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013; 23: 839\u2013852.","DOI":"10.1016\/j.ccr.2013.04.008"},{"key":"ref128","doi-asserted-by":"publisher","unstructured":"Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nature Medicine. 2016; 22: 128\u2013134.","DOI":"10.1038\/nm.4036"},{"key":"ref129","doi-asserted-by":"publisher","unstructured":"Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genetics. 2010; 42: 722\u2013726.","DOI":"10.1038\/ng.621"},{"key":"ref130","doi-asserted-by":"publisher","unstructured":"Nikoloski G, Langemeijer SMC, Kuiper RP, Knops R, Massop M, T\u00f6nnissen ERLTM, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nature Genetics. 2010; 42: 665\u2013667.","DOI":"10.1038\/ng.620"},{"key":"ref131","doi-asserted-by":"publisher","unstructured":"Nishioka C, Ikezoe T, Yang J, Yokoyama A. BCR\/ABL increases EZH2 levels which regulates XIAP expression via miRNA-219 in chronic myeloid leukemia cells. Leukemia Research. 2016; 45: 24\u201332.","DOI":"10.1016\/j.leukres.2016.03.012"},{"key":"ref132","doi-asserted-by":"publisher","unstructured":"Khan SN, Jankowska AM, Mahfouz R, Dunbar AJ, Sugimoto Y, Hosono N, et al. Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies. Leukemia. 2013; 27: 1301\u20131309.","DOI":"10.1038\/leu.2013.80"},{"key":"ref133","doi-asserted-by":"publisher","unstructured":"Kamminga LM, Bystrykh LV, de Boer A, Houwer S, Douma J, Weersing E, et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood. 2006; 107: 2170\u20132179.","DOI":"10.1182\/blood-2005-09-3585"},{"key":"ref134","doi-asserted-by":"publisher","unstructured":"Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, et al. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Molecular Cancer Therapeutics. 2009; 8: 1579\u20131588.","DOI":"10.1158\/1535-7163.MCT-09-0013"},{"key":"ref135","doi-asserted-by":"publisher","unstructured":"Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes & Development. 2007; 21: 1050\u20131063.","DOI":"10.1101\/gad.1524107"},{"key":"ref136","doi-asserted-by":"publisher","unstructured":"Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature Chemical Biology. 2012; 8: 890\u2013896.","DOI":"10.1038\/nchembio.1084"},{"key":"ref137","doi-asserted-by":"publisher","unstructured":"McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012; 492: 108\u2013112.","DOI":"10.1038\/nature11606"},{"key":"ref138","doi-asserted-by":"publisher","unstructured":"Verma SK, Tian X, LaFrance LV, Duquenne C, Suarez DP, Newlander KA, et al. Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Medicinal Chemistry Letters. 2012; 3: 1091\u20131096.","DOI":"10.1021\/ml3003346"},{"key":"ref139","doi-asserted-by":"publisher","unstructured":"Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Molecular Cancer Therapeutics. 2014; 13: 842\u2013854.","DOI":"10.1158\/1535-7163.MCT-13-0773"},{"key":"ref140","doi-asserted-by":"publisher","unstructured":"Xu B, On DM, Ma A, Parton T, Konze KD, Pattenden SG, et al. Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood. 2015; 125: 346\u2013357.","DOI":"10.1182\/blood-2014-06-581082"},{"key":"ref141","doi-asserted-by":"publisher","unstructured":"Zhang H, Qi J, Reyes JM, Li L, Rao PK, Li F, et al. Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer. Cancer Discovery. 2016; 6: 1006\u20131021.","DOI":"10.1158\/2159-8290.CD-16-0164"},{"key":"ref142","doi-asserted-by":"publisher","unstructured":"Yu T, Wang Y, Hu Q, Wu W, Wu Y, Wei W, et al. The EZH2 inhibitor GSK343 suppresses cancer stem-like phenotypes and reverses mesenchymal transition in glioma cells. Oncotarget. 2017; 8: 98348\u201398359.","DOI":"10.18632\/oncotarget.21311"},{"key":"ref143","doi-asserted-by":"publisher","unstructured":"Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, Tay KG, et al. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood. 2011; 118: 2830\u20132839.","DOI":"10.1182\/blood-2010-07-294827"},{"key":"ref144","doi-asserted-by":"publisher","unstructured":"Tanaka S, Miyagi S, Sashida G, Chiba T, Yuan J, Mochizuki-Kashio M, et al. Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia. Blood. 2012; 120: 1107\u20131117.","DOI":"10.1182\/blood-2011-11-394932"},{"key":"ref145","doi-asserted-by":"publisher","unstructured":"Scott MT, Korfi K, Saffrey P, Hopcroft LEM, Kinstrie R, Pellicano F, et al. Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition. Cancer Discovery. 2016; 6: 1248\u20131257.","DOI":"10.1158\/2159-8290.CD-16-0263"},{"key":"ref146","doi-asserted-by":"publisher","unstructured":"Xie H, Peng C, Huang J, Li BE, Kim W, Smith EC, et al. Chronic Myelogenous Leukemia- Initiating Cells Require Polycomb Group Protein EZH2. Cancer Discovery. 2016; 6: 1237\u20131247.","DOI":"10.1158\/2159-8290.CD-15-1439"},{"key":"ref147","doi-asserted-by":"publisher","unstructured":"Drusbosky LM, Singh NK, Hawkins KE, Salan C, Turcotte M, Wise EA, et al. A genomics-informed computational biology platform prospectively predicts treatment responses in AML and MDS patients. Blood Advances. 2019; 3: 1837\u20131847.","DOI":"10.1182\/bloodadvances.2018028316"},{"key":"ref148","doi-asserted-by":"publisher","unstructured":"Giustacchini A, Thongjuea S, Barkas N, Woll PS, Povinelli BJ, Booth CAG, et al. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nature Medicine. 2017; 23: 692\u2013702.","DOI":"10.1038\/nm.4336"},{"key":"ref149","doi-asserted-by":"publisher","unstructured":"Patterson SD, Copland M. The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities. Current Hematologic Malignancy Reports. 2023; 18: 19\u201332.","DOI":"10.1007\/s11899-023-00688-6"},{"key":"ref150","doi-asserted-by":"publisher","unstructured":"Zhang Y, Jiang S, He F, Tian Y, Hu H, Gao L, et al. Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML. Genome Biology. 2023; 24: 199.","DOI":"10.1186\/s13059-023-03031-7"},{"key":"ref151","doi-asserted-by":"publisher","unstructured":"Huuhtanen J, Adnan-Awad S, Theodoropoulos J, Forst\u00e9n S, Warfvinge R, Dufva O, et al. Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation. Leukemia. 2024; 38: 109\u2013125.","DOI":"10.1038\/s41375-023-02074-w"},{"key":"ref152","doi-asserted-by":"publisher","unstructured":"van Galen P, Hovestadt V, Wadsworth Ii MH, Hughes TK, Griffin GK, Battaglia S, et al. Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity. Cell. 2019; 176: 1265\u20131281.e24.","DOI":"10.1016\/j.cell.2019.01.031"},{"key":"ref153","doi-asserted-by":"publisher","unstructured":"Ito K, Ito K. Leukemia Stem Cells as a Potential Target to Achieve Therapy-Free Remission in Chronic Myeloid Leukemia. 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