{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:26:52Z","timestamp":1785392812715,"version":"3.55.0"},"reference-count":48,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T00:00:00Z","timestamp":1700697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ADPS"},{"name":"Conseil D\u00e9partemental du Haut\u2013Rhin"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease characterized by the presence of the BCR-ABL fusion gene, which results from the Philadelphia chromosome. Since the introduction of tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM), the clinical outcomes for patients with CML have improved significantly. However, IM resistance remains the major clinical challenge for many patients, underlining the need to develop new drugs for the treatment of CML. The basis of CML cell resistance to this drug is unclear, but the appearance of additional genetic alterations in leukemic stem cells (LSCs) is the most common cause of patient relapse. However, several groups have identified a rare subpopulation of CD34+ stem cells in adult patients that is present mainly in the bone marrow and is more immature and pluripotent; these cells are also known as very small embryonic-like stem cells (VSELs). The uncontrolled proliferation and a compromised differentiation possibly initiate their transformation to leukemic VSELs (LVSELs). Their nature and possible involvement in carcinogenesis suggest that they cannot be completely eradicated with IM treatment. In this study, we demonstrated that cells from CML patients with the VSELs phenotype (LVSELs) similarly harbor the fusion protein BCR-ABL and are less sensitive to apoptosis than leukemic HSCs after IM treatment. Thus, IM induces apoptosis and reduces the proliferation and mRNA expression of Ki67 more efficiently in LHSCs than in leukemic LVSELs. Finally, we found that the expression levels of some miRNAs are affected in LVSELs. In addition to the tumor suppressor miR-451, both miR-126 and miR-21, known to be responsible for LSC leukemia-initiating capacity, quiescence, and growth, appear to be involved in IM insensitivity of LVSELs CML cell population. Targeting IM-resistant CML leukemic stem cells by acting via the miRNA pathways may represent a promising therapeutic option.<\/jats:p>","DOI":"10.3390\/ijms242316671","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T11:31:25Z","timestamp":1700739085000},"page":"16671","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Stem Cell Responsiveness to Imatinib in Chronic Myeloid Leukemia"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2966-6386","authenticated-orcid":false,"given":"Rachid","family":"Lahlil","sequence":"first","affiliation":[{"name":"Institut de Recherche en H\u00e9matologie et Transplantation (IRHT), H\u00f4pital du Hasenrain, 87 Avenue d\u2019Altkirch, 68100 Mulhouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Aries","sequence":"additional","affiliation":[{"name":"Institut de Recherche en H\u00e9matologie et Transplantation (IRHT), H\u00f4pital du Hasenrain, 87 Avenue d\u2019Altkirch, 68100 Mulhouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Scrofani","sequence":"additional","affiliation":[{"name":"Institut de Recherche en H\u00e9matologie et Transplantation (IRHT), H\u00f4pital du Hasenrain, 87 Avenue d\u2019Altkirch, 68100 Mulhouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Zanetti","sequence":"additional","affiliation":[{"name":"Institut de Recherche en H\u00e9matologie et Transplantation (IRHT), H\u00f4pital du Hasenrain, 87 Avenue d\u2019Altkirch, 68100 Mulhouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desline","family":"Hennequin","sequence":"additional","affiliation":[{"name":"Institut de Recherche en H\u00e9matologie et Transplantation (IRHT), H\u00f4pital du Hasenrain, 87 Avenue d\u2019Altkirch, 68100 Mulhouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2175-6785","authenticated-orcid":false,"given":"Bernard","family":"Dr\u00e9nou","sequence":"additional","affiliation":[{"name":"Institut de Recherche en H\u00e9matologie et Transplantation (IRHT), H\u00f4pital du Hasenrain, 87 Avenue d\u2019Altkirch, 68100 Mulhouse, France"},{"name":"Laboratoire d\u2019H\u00e9matologie, Groupe Hospitalier de la R\u00e9gion de Mulhouse Sud-Alsace, H\u00f4pital E. Muller, 20 Avenue de Dr. Laennec, 68100 Mulhouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1016\/S0140-6736(21)01204-6","article-title":"Chronic Myeloid Leukaemia","volume":"398","author":"Cortes","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S0140-6736(02)07679-1","article-title":"BCR-ABL Gene Mutations in Relation to Clinical Resistance of Philadelphia-Chromosome-Positive Leukaemia to STI571: A Prospective Study","volume":"359","author":"Schneller","year":"2002","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Amarante-Mendes, G.P., Rana, A., Datoguia, T.S., Hamerschlak, N., and Brumatti, G. (2022). BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14010215"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/sj.leu.2404171","article-title":"A Population of Very Small Embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ Stem Cells Identified in Adult Bone Marrow","volume":"20","author":"Kucia","year":"2006","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1038\/leu.2017.148","article-title":"Why Are Hematopoietic Stem Cells so \u2018Sexy\u2019? On a Search for Developmental Explanation","volume":"31","author":"Ratajczak","year":"2017","journal-title":"Leukemia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1172\/JCI35721","article-title":"Human Chronic Myeloid Leukemia Stem Cells Are Insensitive to Imatinib despite Inhibition of BCR-ABL Activity","volume":"121","author":"Corbin","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5565","DOI":"10.1182\/blood-2010-12-327437","article-title":"Persistence of Leukemia Stem Cells in Chronic Myelogenous Leukemia Patients in Prolonged Remission with Imatinib Treatment","volume":"118","author":"Chu","year":"2011","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/bjh.12364","article-title":"MicroRNAs in Myeloid Malignancies","volume":"162","author":"Gordon","year":"2013","journal-title":"Br. J. Haematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1080\/10428194.2016.1243676","article-title":"miRNAs in Chronic Myeloid Leukemia: Small Molecules, Essential Function","volume":"58","year":"2017","journal-title":"Leuk. Lymphoma"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rudich, A., Garzon, R., and Dorrance, A. (2022). Non-Coding RNAs Are Implicit in Chronic Myeloid Leukemia Therapy Resistance. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012271"},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1177\/1535370215584940","article-title":"The Cell Cycle- and Insulin-Signaling-Inhibiting miRNA Expression Pattern of Very Small Embryonic-like Stem Cells Contributes to Their Quiescent State","volume":"240","author":"Maj","year":"2015","journal-title":"Exp. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s12015-018-9821-1","article-title":"VSELs Maintain Their Pluripotency and Competence to Differentiate after Enhanced Ex Vivo Expansion","volume":"14","author":"Lahlil","year":"2018","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_14","first-page":"769","article-title":"Expression of P57(KIP2) in Hepatocellular Carcinoma: Relationship between Tumor Differentiation and Patient Survival","volume":"20","author":"Nakai","year":"2002","journal-title":"Int. J. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1093\/carcin\/bgq211","article-title":"p57Kip2 Is a Downstream Effector of BCR-ABL Kinase Inhibitors in Chronic Myelogenous Leukemia Cells","volume":"32","author":"Borriello","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1038\/sj.cdd.4402158","article-title":"The Cell Cycle Inhibitor p57Kip2 Promotes Cell Death via the Mitochondrial Apoptotic Pathway","volume":"14","author":"Vlachos","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Taniguchi, M., Fukunaka, A., Hagihara, M., Watanabe, K., Kamino, S., Kambe, T., Enomoto, S., and Hiromura, M. (2013). Essential Role of the Zinc Transporter ZIP9\/SLC39A9 in Regulating the Activations of Akt and Erk in B-Cell Receptor Signaling Pathway in DT40 Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058022"},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.bcmd.2014.02.008","article-title":"ApoptomiRs Expression Modulated by BCR-ABL Is Linked to CML Progression and Imatinib Resistance","volume":"53","author":"Ferreira","year":"2014","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1007\/s10926-019-09832-7","article-title":"Sustainable Return to Work: A Systematic Review Focusing on Personal and Social Factors","volume":"29","author":"Etuknwa","year":"2019","journal-title":"J. Occup. Rehabil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1136\/jim-2020-001563","article-title":"Circulating miR-146a Expression Predicts Early Treatment Response to Imatinib in Adult Chronic Myeloid Leukemia","volume":"69","author":"Habib","year":"2021","journal-title":"J. Investig. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.cbi.2018.06.006","article-title":"microRNA-199a\/b-5p Enhance Imatinib Efficacy via Repressing WNT2 Signaling-Mediated Protective Autophagy in Imatinib-Resistant Chronic Myeloid Leukemia Cells","volume":"291","author":"Chen","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Martins, J.R.B., Moraes, L.N., Cury, S.S., Capannacci, J., Carvalho, R.F., Nogueira, C.R., Hokama, N.K., and Hokama, P.O.M. (2021). MiR-125a-3p and MiR-320b Differentially Expressed in Patients with Chronic Myeloid Leukemia Treated with Allogeneic Hematopoietic Stem Cell Transplantation and Imatinib Mesylate. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910216"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.jamcollsurg.2020.02.026","article-title":"Consent Including Sexual Dysfunction and Pain with Sexual Activity after Inguinal Hernia Repair?","volume":"230","author":"Shrestha","year":"2020","journal-title":"J. Am. Coll. Surg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1182\/blood-2014-06-581926","article-title":"MicroRNA-486 Regulates Normal Erythropoiesis and Enhances Growth and Modulates Drug Response in CML Progenitors","volume":"125","author":"Wang","year":"2015","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"26","DOI":"10.21037\/sci.2016.06.07","article-title":"Endothelial Progenitor Cells in Hematologic Malignancies","volume":"3","author":"Testa","year":"2016","journal-title":"Stem Cell Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1182\/blood-2004-07-2514","article-title":"Identification of Human Chronic Myelogenous Leukemia Progenitor Cells with Hemangioblastic Characteristics","volume":"105","author":"Fang","year":"2005","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1016\/S0140-6736(00)02241-8","article-title":"Evidence from a Leukaemia Model for Maintenance of Vascular Endothelium by Bone-Marrow-Derived Endothelial Cells","volume":"355","author":"Gunsilius","year":"2000","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1182\/blood.V94.6.2056","article-title":"Isolation of a Highly Quiescent Subpopulation of Primitive Leukemic Cells in Chronic Myeloid Leukemia","volume":"94","author":"Holyoake","year":"1999","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1182\/blood-2016-09-696013","article-title":"The Chronic Myeloid Leukemia Stem Cell: Stemming the Tide of Persistence","volume":"129","author":"Holyoake","year":"2017","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/ajh.21915","article-title":"Characterization of Chronic Myeloid Leukemia Stem Cells","volume":"86","author":"Gerber","year":"2011","journal-title":"Am. J. Hematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1182\/blood.V99.1.319","article-title":"Primitive, Quiescent, Philadelphia-Positive Stem Cells from Patients with Chronic Myeloid Leukemia Are Insensitive to STI571 in Vitro","volume":"99","author":"Graham","year":"2002","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4532","DOI":"10.1182\/blood-2005-07-2947","article-title":"Dasatinib (BMS-354825) Targets an Earlier Progenitor Population than Imatinib in Primary CML but Does Not Eliminate the Quiescent Fraction","volume":"107","author":"Copland","year":"2006","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1158\/0008-5472.CAN-07-6858","article-title":"BCR\/ABL Inhibits Mismatch Repair to Protect from Apoptosis and Induce Point Mutations","volume":"68","author":"Stoklosa","year":"2008","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1080\/03093640701859089","article-title":"BCR\/ABL, DNA Damage and DNA Repair: Implications for New Treatment Concepts","volume":"49","author":"Skorski","year":"2008","journal-title":"Leuk. Lymphoma"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Creff, J., and Besson, A. (2020). Functional Versatility of the CDK Inhibitor p57Kip2. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.584590"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/sj.leu.2403999","article-title":"Transient or Long-Term Silencing of BCR-ABL Alone Induces Cell Cycle and Proliferation Arrest, Apoptosis and Differentiation","volume":"20","author":"Rangatia","year":"2006","journal-title":"Leukemia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.31557\/APJCP.2019.20.8.2379","article-title":"microRNA-21 Expression as Prognostic and Therapeutic Response Marker in Chronic Myeloid Leukaemia Patients","volume":"20","author":"Mirza","year":"2019","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9666","DOI":"10.1038\/s41598-019-46132-9","article-title":"MicroRNA Signature Refine Response Prediction in CML","volume":"9","author":"Alves","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.leukres.2015.07.008","article-title":"Silencing of miR-21 Sensitizes CML CD34+ Stem\/Progenitor Cells to Imatinib-Induced Apoptosis by Blocking PI3K\/AKT Pathway","volume":"39","author":"Wang","year":"2015","journal-title":"Leuk. Res."},{"key":"ref_41","first-page":"955","article-title":"MicroRNA-130a Regulates Cell Malignancy by Targeting RECK in Chronic Myeloid Leukemia","volume":"8","author":"Li","year":"2016","journal-title":"Am. J. Transl. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Abdulmawjood, B., Costa, B., Roma-Rodrigues, C., Baptista, P.V., and Fernandes, A.R. (2021). Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212516"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.gene.2014.03.049","article-title":"Down-Regulation of miR-199b Associated with Imatinib Drug Resistance in 9q34.1 Deleted BCR\/ABL Positive CML Patients","volume":"542","author":"Joshi","year":"2014","journal-title":"Gene"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1159\/000524158","article-title":"MiR-199a-3p Overexpression Suppressed Cell Proliferation and Sensitized Chronic Myeloid Leukaemia Cells to Imatinib by Inhibiting mTOR Signalling","volume":"145","author":"Liu","year":"2022","journal-title":"Acta Haematol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.1182\/blood-2007-07-098749","article-title":"MicroRNA Signatures Associated with Cytogenetics and Prognosis in Acute Myeloid Leukemia","volume":"111","author":"Garzon","year":"2008","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ma, J., Wu, D., Yi, J., Yi, Y., Zhu, X., Qiu, H., Kong, R., Lin, J., Qian, J., and Deng, Z. (2019). MiR-378 Promoted Cell Proliferation and Inhibited Apoptosis by Enhanced Stem Cell Properties in Chronic Myeloid Leukemia K562 Cells. Biomed. Pharmacother., 112.","DOI":"10.1016\/j.biopha.2019.108623"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/j.yexcr.2013.02.002","article-title":"miR-29b Suppresses CML Cell Proliferation and Induces Apoptosis via Regulation of BCR\/ABL1 Protein","volume":"319","author":"Li","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bhartiya, D., Jha, N., Tripathi, A., and Tripathi, A. (2023). Very Small Embryonic-like Stem Cells Have the Potential to Win the Three-Front War on Tissue Damage, Cancer, and Aging. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.1061022"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16671\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:28:30Z","timestamp":1760131710000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16671"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,23]]},"references-count":48,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242316671"],"URL":"https:\/\/doi.org\/10.3390\/ijms242316671","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,23]]}}}