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Acute myeloid leukemia

Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent

Leukemia volume 29, pages 2277–2284 (2015)Cite this article

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Abstract

We recently identified that the MEK/ERK1/2 pathway synergized with retinoic acid (RA) to restore both transcriptional activity and RA-induced differentiation in RA-resistant acute promyelocytic leukemia (APL) cells. To target the MEK/ERK pathway, we identified glycogen synthase kinase-3β (GSK-3β) inhibitors including lithium chloride (LiCl) as activators of this pathway in APL cells. Using NB4 (RA-sensitive) and UF-1 (RA-resistant) APL cell lines, we observed that LiCl as well as synthetic GSK-3β inhibitors decreased proliferation, induced apoptosis and restored, in RA-resistant cells, the expression of RA target genes and the RA-induced differentiation. Inhibition of the MEK/ERK1/2 pathway abolished these effects. These results were corroborated in primary APL patient cells and translated in vivo using an APL preclinical mouse model in which LiCl given alone was as efficient as RA in increasing survival of leukemic mice compared with untreated mice. When LiCl was combined with RA, we observed a significant survival advantage compared with mice treated by RA alone. In this work, we demonstrate that LiCl, a well-tolerated agent in humans, has antileukemic activity in APL and that it has the potential to restore RA-induced transcriptional activation and differentiation in RA-resistant APL cells in an MEK/ERK-dependent manner.

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Acknowledgements

This study was supported by a grant from Ligue Contre le Cancer (RS10/75-61) and an ANR Grant BiotecS 2009 ‘GSKforonco’. We thank Targeon SAS for the kind gift of GSK-3β inhibitors. We are grateful to Gil Letort for precious technical help.

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Authors and Affiliations

  1. Service de Biologie Cellulaire AP-HP Hopital Saint-Louis, Paris, France

    F Zassadowski, C Chomienne & B Cassinat

  2. Inserm UMR-S 1131, Hopital Saint-Louis, Paris, France

    F Zassadowski, K Pokorna, N Ferre, F Guidez, L Llopis, O Chourbagi, R Ann Padua, M Pla, C Chomienne & B Cassinat

  3. Departement d'Experimentation Animale, IUH, Universite Paris-Diderot, Paris, France

    M Chopin & M Pla

  4. Laboratoire de Toxicologie Biologique, AP-HP Hopital Lariboisiere, Paris, France

    J Poupon

  5. Service d’Hematologie Senior, AP-HP, Hopital Saint-Louis, Paris, France

    P Fenaux

  6. Universite Paris-Diderot, Paris, France

    C Chomienne

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  1. F Zassadowski
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Correspondence to B Cassinat.

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Zassadowski, F., Pokorna, K., Ferre, N. et al. Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent. Leukemia 29, 2277–2284 (2015). https://doi.org/10.1038/leu.2015.159

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