In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features
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ORIGINAL RESEARCH ARTICLE
In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features Ignazia Tusa1 · Giulia Cheloni1 · Martina Poteti1 · Angela Silvano1 · Alessandro Tubita1 · Zoe Lombardi1 · Antonella Gozzini2 · Roberto Caporale3 · Barbara Scappini2 · Persio Dello Sbarba1 · Elisabetta Rovida1
© The Author(s) 2020
Abstract Background The development of molecularly tailored therapeutic agents such as the BCR/ABL-active tyrosine kinase inhibitors (TKi) resulted in an excellent treatment option for chronic myeloid leukemia (CML) patients. However, following TKi discontinuation, disease relapses in 40–60% of patients, an occurrence very likely due to the persistence of leukemic stem cells that are scarcely sensitive to TKi. Nevertheless, TKi are still the only current treatment option for CML patients. Objective The aim of this study was to compare the effects of TKi belonging to different generations, imatinib and ponatinib (first and third generation, respectively), on progenitor/stem cell expansion potential and markers. Patients and Methods We used stabilized CML cell lines (KCL22, K562 and LAMA-84 cells), taking advantage of the previous demonstration of ours that cell lines contain cell subsets endowed with progenitor/stem cell properties. Primary cells explanted from CML patients were also used. The effects of TKi on the expression of stem cell related genes were compared by quantitative PCR. Flow cytometry was performed to evaluate aldehyde-dehydrogenase (ALDH) activity and the expression of cluster of differentiation (CD) cell surface hematopoietic stem cell markers. Progenitor/stem-cell potential was estimated by serial colony formation ability (CFA) assay. Results Ponatinib was more effective than imatinib for the reduction of cells with ALDH activity and progenitor/stem-cell potential of CML patient-derived cells and cell lines. Furthermore, ponatinib was more effective than imatinib in reducing the percentage of CD26-expressing cells in primary CML cells, whereas imatinib and ponatinib showed similar efficacy on KCL22 cells. Both drugs strongly upregulated NANOG and SOX2 in CML cell lines, but in KCL22 cells this upregulation was significantly lower with ponatinib than with imatinib, an outcome compatible with a lower level of enrichment of the stem-cell compartment upon ponatinib treatment. Conclusion Ponatinib seems to target CML progenitor/stem cells better than imatinib.
1 Introduction Ignazia Tusa and Giulia Cheloni contributed equally to the work. Persio Dello Sbarba and Elisabetta Rovida are co-last authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11523-020-00741-x) contains supplementary material, which is available to authorized users. * Persio Dello Sbarba [email protected] * Elisabetta Rovida [email protected] 1
The pathogenesis of chronic myeloid leukemia (CML) is centered on the expression of the BCR/ABL oncoprotein, a constitutively active tyrosine kinase [1]. The
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