Human telomerase reverse transcriptase depletion potentiates the growth-inhibitory activity of imatinib in chronic myeloid leukemia stem cells.

Abstract

Although tyrosine kinase inhibitors (TKIs) revolutionized the management of chronic myeloid leukemia (CML), resistance against TKIs and leukemia stem cell (LSC) persistence remain a clinical concern. Therefore, new therapeutic strategies combining conventional and novel therapies are urgently needed. Since telomerase is involved in oncogenesis and tumor progression but is silent in most human normal somatic cells, it may be an interesting target for CML therapy by selectively targeting cancer cells while minimizing effects on normal cells. Here, we report that hTERT expression is associated with CML disease progression. We also provide evidence that hTERT-deficient K-562 cells do not display telomere shortening and that telomere length is maintained through the ALT pathway. Furthermore, we show that hTERT depletion exerts a growth-inhibitory effect in K-562 cells and potentiates imatinib through alteration of cell cycle progression leading to a senescence-like phenotype. Finally, we demonstrate that hTERT depletion potentiates the imatinib-induced reduction of the ALDH+-LSC population. Altogether, our results suggest that the combination of telomerase and TKI should be considered as an attractive strategy to treat CML patients to eradicate cancer cells and prevent relapse by targeting LSCs.

• Authors: Cindy Grandjenette, Michael Schnekenburger, Anthoula Gaigneaux, Déborah Gérard, Christo Christov, Aloran Mazumder, Mario Dicato, Marc Diederich
• Journal: Cancer letters (Cancer Lett) Vol. 469 Pg. 468-480 (01 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 31734352 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Imatinib Mesylate
• Aldehyde Dehydrogenase 1 Family
• Fusion Proteins, bcr-abl
• TERT protein, human
• Telomerase

Topics

• Aldehyde Dehydrogenase 1 Family (genetics)
• Apoptosis (drug effects)
• Carcinogenesis (drug effects)
• Cell Lineage (genetics)
• Cell Proliferation (drug effects)
• Disease Progression
• Drug Resistance, Neoplasm (genetics)
• Female
• Fusion Proteins, bcr-abl (genetics)
• Humans
• Imatinib Mesylate (pharmacology)
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, pathology)
• Male
• Neoplastic Stem Cells (drug effects, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Telomerase (genetics)