{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:35:57Z","timestamp":1789050957409,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Thermo Fisher Scientific, Eugene, Oregon, USA","award":["PI\/17\/0575"],"award-info":[{"award-number":["PI\/17\/0575"]}]},{"name":"Thermo Fisher Scientific, Eugene, Oregon, USA","award":["PI 20\/00531"],"award-info":[{"award-number":["PI 20\/00531"]}]},{"name":"Thermo Fisher Scientific, Eugene, Oregon, USA","award":["2021 SGR 00560"],"award-info":[{"award-number":["2021 SGR 00560"]}]},{"name":"Thermo Fisher Scientific, Eugene, Oregon, USA","award":["2021 SGR 00002"],"award-info":[{"award-number":["2021 SGR 00002"]}]},{"name":"Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain","award":["PI\/17\/0575"],"award-info":[{"award-number":["PI\/17\/0575"]}]},{"name":"Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain","award":["PI 20\/00531"],"award-info":[{"award-number":["PI 20\/00531"]}]},{"name":"Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain","award":["2021 SGR 00560"],"award-info":[{"award-number":["2021 SGR 00560"]}]},{"name":"Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Spain","award":["2021 SGR 00002"],"award-info":[{"award-number":["2021 SGR 00002"]}]},{"name":"European Regional Development Fund","award":["PI\/17\/0575"],"award-info":[{"award-number":["PI\/17\/0575"]}]},{"name":"European Regional Development Fund","award":["PI 20\/00531"],"award-info":[{"award-number":["PI 20\/00531"]}]},{"name":"European Regional Development Fund","award":["2021 SGR 00560"],"award-info":[{"award-number":["2021 SGR 00560"]}]},{"name":"European Regional Development Fund","award":["2021 SGR 00002"],"award-info":[{"award-number":["2021 SGR 00002"]}]},{"name":"CERCA, Centres de Recerca de Catalunya","award":["PI\/17\/0575"],"award-info":[{"award-number":["PI\/17\/0575"]}]},{"name":"CERCA, Centres de Recerca de Catalunya","award":["PI 20\/00531"],"award-info":[{"award-number":["PI 20\/00531"]}]},{"name":"CERCA, Centres de Recerca de Catalunya","award":["2021 SGR 00560"],"award-info":[{"award-number":["2021 SGR 00560"]}]},{"name":"CERCA, Centres de Recerca de Catalunya","award":["2021 SGR 00002"],"award-info":[{"award-number":["2021 SGR 00002"]}]},{"name":"La Caixa Foundation, Obra Social la Caixa, Fundaci\u00f3 Internacional Josep Carreras, Barcelona, Spain","award":["PI\/17\/0575"],"award-info":[{"award-number":["PI\/17\/0575"]}]},{"name":"La Caixa Foundation, Obra Social la Caixa, Fundaci\u00f3 Internacional Josep Carreras, Barcelona, Spain","award":["PI 20\/00531"],"award-info":[{"award-number":["PI 20\/00531"]}]},{"name":"La Caixa Foundation, Obra Social la Caixa, Fundaci\u00f3 Internacional Josep Carreras, Barcelona, Spain","award":["2021 SGR 00560"],"award-info":[{"award-number":["2021 SGR 00560"]}]},{"name":"La Caixa Foundation, Obra Social la Caixa, Fundaci\u00f3 Internacional Josep Carreras, Barcelona, Spain","award":["2021 SGR 00002"],"award-info":[{"award-number":["2021 SGR 00002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Leukemic stem cells (LSCs) possess similar characteristics to normal hematopoietic stem cells, including self-renewal capacity, quiescence, ability to initiate leukemia, and drug resistance. These cells play a significant role in leukemia relapse, persisting even after apparent remission. LSCs were first described in 1994 by Lapidot et al. Although they have been extensively studied in acute leukemia, more LSC research is still needed in chronic lymphocytic leukemia (CLL) to understand if reduced apoptosis in mature cells should still be considered as the major cause of this disease. Here, we provide new evidence suggesting the existence of stem-like cell populations in CLL, which may help to understand the disease as well as to develop effective treatments. In this study, we identified a potential leukemic stem cell subpopulation using the tetraploid CLL cell line I83. This subpopulation is characterized by diploid cells that were capable of generating the I83 tetraploid population. Furthermore, we adapted a novel flow cytometry analysis protocol to detect CLL subpopulations with stem cell properties in peripheral blood samples and primary cultures from CLL patients. These cells were identified by their co-expression of CD19 and CD5, characteristic markers of CLL cells. As previously described, increased alkaline phosphatase (ALP) activity is indicative of stemness and pluripotency. Moreover, we used this method to investigate the potential synergistic effect of curcumin in combination with fludarabine and ibrutinib to deplete this subpopulation. Our results confirmed the effectiveness of this ALP-based analysis protocol in detecting and monitoring leukemic stem-like cells in CLL. This analysis also identified limitations in eradicating these populations using in vitro testing. Furthermore, our findings demonstrated that curcumin significantly enhanced the effects of fludarabine and ibrutinib on the leukemic fraction, exhibiting synergistic effects (combination drug index, CDI 0.97 and 0.37, respectively). Our results lend support to the existence of potential stem-like populations in CLL cell lines, and to the idea that curcumin could serve as an effective adjuvant in therapies aimed at eliminating these populations and improving treatment efficacy.<\/jats:p>","DOI":"10.3390\/ijms25041994","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T03:47:09Z","timestamp":1707277629000},"page":"1994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Persistence of Chronic Lymphocytic Leukemia Stem-like Populations under Simultaneous In Vitro Treatment with Curcumin, Fludarabine, and Ibrutinib: Implications for Therapy Resistance"],"prefix":"10.3390","volume":"25","author":[{"given":"\u00c0ngel","family":"Bistu\u00e9-Rovira","sequence":"first","affiliation":[{"name":"Departament de Farmacologia, Terap\u00e8utica i Toxicologia, Universitat Aut\u00f2noma de Barcelona (UAB), 08193 Cerdanyola del Vall\u00e8s, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9867-4393","authenticated-orcid":false,"given":"Laura G.","family":"Rico","sequence":"additional","affiliation":[{"name":"Germans Trias i Pujol Research Institute (IGTP), Universitat Aut\u00f2noma de Barcelona (UAB), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Bardina","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Junc\u00e0","sequence":"additional","affiliation":[{"name":"MDS Group, Institut de Recerca Contra la Leuc\u00e8mia Josep Carreras, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Granada","sequence":"additional","affiliation":[{"name":"MDS Group, Institut de Recerca Contra la Leuc\u00e8mia Josep Carreras, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolene A.","family":"Bradford","sequence":"additional","affiliation":[{"name":"Thermo Fisher Scientific, Fort Collins, CO 80524, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Ward","sequence":"additional","affiliation":[{"name":"Thermo Fisher Scientific, Fort Collins, CO 80524, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2118-9231","authenticated-orcid":false,"given":"Roser","family":"Salvia","sequence":"additional","affiliation":[{"name":"Germans Trias i Pujol Research Institute (IGTP), Universitat Aut\u00f2noma de Barcelona (UAB), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3251-2161","authenticated-orcid":false,"given":"Francesc","family":"Sol\u00e9","sequence":"additional","affiliation":[{"name":"MDS Group, Institut de Recerca Contra la Leuc\u00e8mia Josep Carreras, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Petriz","sequence":"additional","affiliation":[{"name":"Germans Trias i Pujol Research Institute (IGTP), Universitat Aut\u00f2noma de Barcelona (UAB), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1056\/NEJMra061808","article-title":"Cancer stem cells","volume":"355","author":"Jordan","year":"2006","journal-title":"N. 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