In Vitro Comparison of the Effects of Imatinib and Ponatinib on Chronic Myeloid Leukemia Progenitor/Stem Cell Features

Overview

Journal Target Oncol

Specialty Oncology

Date 2020 Aug 12

PMID 32780298

Citations 4

Authors

Ignazia Tusa

Giulia Cheloni

Martina Poteti

Angela Silvano

Alessandro Tubita

Zoe Lombardi

Antonella Gozzini

Roberto Caporale

Barbara Scappini

Persio Dello Sbarba

Elisabetta Rovida

Affiliations

Soon will be listed here.

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.

Citing Articles

Tyrosine Kinase Inhibitor Therapy Enhances Stem Cells Profile and May Contribute to Survival of Chronic Myeloid Leukemiastem Cells.

Rocco S, Maglione A, Schiavo V, Ferrando A, Fava C, Cilloni D J Clin Med. 2025; 14(2).

PMID: 39860398 PMC: 11765529. DOI: 10.3390/jcm14020392.

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives.

Barreto I, DE Pinho Pessoa F, Machado C, da Costa Pantoja L, Ribeiro R, Lopes G Front Oncol. 2022; 12:931050.

PMID: 35814466 PMC: 9270022. DOI: 10.3389/fonc.2022.931050.

Rotating between ponatinib and imatinib temporarily increases the efficacy of imatinib as shown in a chronic myeloid leukaemia model.

Lindstrom H, Friedman R Sci Rep. 2022; 12(1):5164.

PMID: 35338182 PMC: 8956613. DOI: 10.1038/s41598-022-09048-5.

From Donor to the Lab: A Fascinating Journey of Primary Cell Lines.

Richter M, Piwocka O, Musielak M, Piotrowski I, Suchorska W, Trzeciak T Front Cell Dev Biol. 2021; 9:711381.

PMID: 34395440 PMC: 8356673. DOI: 10.3389/fcell.2021.711381.

Reporters of Cancer Stem Cells as a Tool for Drug Discovery.

Mohan A, Raj R R, Mohan G, K P P, Maliekal T Front Oncol. 2021; 11:669250.

PMID: 33968778 PMC: 8100607. DOI: 10.3389/fonc.2021.669250.

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