Persistence of Chronic Lymphocytic Leukemia Stem-like Populations under Simultaneous In Vitro Treatment with Curcumin, Fludarabine, and Ibrutinib : Implications for Therapy Resistance
Bistué Rovira, Àngel (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
G. Rico, Laura (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Bardina, Jorge (Vall d'Hebron Institut d'Oncologia)
Junca, Jordi (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Granada, Isabel (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Bradford, Jolene A. (Thermo Fisher Scientific (Estats Units d'Amèrica))
Ward, Michael D. (Thermo Fisher Scientific (Estats Units d'Amèrica))
Salvia, Roser (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Sole, F (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Petriz, Jordi (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)

Date:	2024
Abstract:	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.
Grants:	Ministerio de Economía, Industria y Competitividad PI/17/0575 Ministerio de Economía, Industria y Competitividad PI 20/00531
Note:	Altres ajuts: (2021 SGR 00560; 2021 SGR 00002)
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Curcumin ; CLL ; LSCs ; Flow cytometry ; Stem-like ; Alkaline phosphatase
Published in:	International journal of molecular sciences, Vol. 25, Num. 4 (february 2024) , ISSN 1422-0067

DOI: 10.3390/ijms25041994
PMID: 38396682

18 p, 2.0 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles