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Chronic myelogenous leukemia

Effect of tyrosine kinase inhibitors on stemness in normal and chronic myeloid leukemia cells

Leukemia volume 31, pages 65–74 (2017)Cite this article

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Abstract

Although tyrosine kinase inhibitors (TKIs) efficiently cure chronic myeloid leukemia (CML), they can fail to eradicate CML stem cells (CML-SCs). The mechanisms responsible for CML-SC survival need to be understood for designing therapies. Several previous studies suggest that TKIs could modulate CML-SC quiescence. Unfortunately, CML-SCs are insufficiently available. Induced pluripotent stem cells (iPSCs) offer a promising alternative. In this work, we used iPSCs derived from CML patients (Ph+). Ph+ iPSC clones expressed lower levels of stemness markers than normal iPSCs. BCR–ABL1 was found to be involved in stemness regulation and ERK1/2 to have a key role in the signaling pathway. TKIs unexpectedly promoted stemness marker expression in Ph+ iPSC clones. Imatinib also retained quiescence and induced stemness gene expression in CML-SCs. Our results suggest that TKIs might have a role in residual disease and confirm the need for a targeted therapy different from TKIs that could overcome the stemness-promoting effect caused by TKIs. Interestingly, a similar pro-stemness effect was observed in normal iPSCs and hematopoietic SCs. These findings could help to explain CML resistance mechanisms and the teratogenic side-effects of TKIs in embryonic cells.

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Acknowledgements

We thank the Bordeaux vectorology platform (Véronique Guyonnet Duperat, Alice Bibeyran, Quentin Simounet) and the Bordeaux cytometry platform (Vincent Pitard and Santiago Gonzalez). We are grateful to Anne-Sophie Espadinha, Elodie Laharanne, Olivier Mansier, Eric Lippert, Jean Max Pasquet, Valerie Prouzet-Mauléon, Valerie Lagarde, Francois Moisan for their technical help and/or for providing reagents. We thank Etablissement Français du Sang for providing CML cytapheresis and Maison de Santé Protestante de Bordeaux-Bagatelle Hospital for providing umbilical cord blood samples. AB and FMG are supported by a grant from the Ligue Dordogne Contre le Cancer, LC is supported by a fellowship from INSERM/Region Aquitaine, F-XM is supported by SIRIC Brio. AB, FMG and F-XM are supported by a grant from Fondation de France.

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Author notes

  1. F Moreau-Gaudry and A Bedel: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm U1035, Biothérapies des Maladies Génétiques et Cancers, Bordeaux, France

    L Charaf, F-X Mahon, I Lamrissi-Garcia, I Moranvillier, F Beliveau, B Cardinaud, S Dabernat, H de Verneuil, F Moreau-Gaudry & A Bedel

  2. Université de Bordeaux, FR TransBiomed, Bordeaux, France

    L Charaf, F-X Mahon, I Lamrissi-Garcia, I Moranvillier, B Cardinaud, S Dabernat, H de Verneuil, F Moreau-Gaudry & A Bedel

  3. Laboratoire d’Excellence GR-Ex, Bordeaux, France

    L Charaf, I Lamrissi-Garcia, I Moranvillier, F Beliveau, S Dabernat, H de Verneuil, F Moreau-Gaudry & A Bedel

  4. Pôle de Biologie et Pathologie CHU Bordeaux, Bordeaux, France

    F-X Mahon, S Dabernat, H de Verneuil, F Moreau-Gaudry & A Bedel

  5. Institut Bergonie, SIRIC BRIO, Bordeaux, France

    F-X Mahon

  6. Institut Polytechnique de Bordeaux, Talence, France

    B Cardinaud

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  1. L Charaf
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Correspondence to F Moreau-Gaudry.

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Charaf, L., Mahon, FX., Lamrissi-Garcia, I. et al. Effect of tyrosine kinase inhibitors on stemness in normal and chronic myeloid leukemia cells. Leukemia 31, 65–74 (2017). https://doi.org/10.1038/leu.2016.154

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