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Sensitivity and Resistance to Therapy

BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

Leukemia volume 22, pages 791–799 (2008)Cite this article

Abstract

Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL+ leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K+T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.

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Acknowledgements

This study was supported by the Cancéropole Nord-Ouest, the Ligue Nationale Contre le Cancer (Equipe labellisée) and the Fondation de France. JL was supported by a grant from Fondation pour la Recherche Médicale and Institut de Recherche sur le Cancer de Lille.

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Authors and Affiliations

  1. INSERM, Unité 837, Equipe 3, Institut de Recherche sur le Cancer de Lille, Lille, France

    J Liu, S Joha, T Idziorek, S Corm, D Hetuin, C Preudhomme & B Quesnel

  2. Institut Fédératif de Recherche 114, Université de Lille 2, Lille, France

    T Idziorek, S Corm, C Preudhomme & B Quesnel

  3. Service des Maladies du Sang, Centre Hospitalier et Universitaire de Lille, Lille, France

    S Corm & B Quesnel

  4. Laboratoire d'Hématologie, Centre Hospitalier et Universitaire de Lille, Lille, France

    N Philippe & C Preudhomme

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Correspondence to B Quesnel.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Liu, J., Joha, S., Idziorek, T. et al. BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism. Leukemia 22, 791–799 (2008). https://doi.org/10.1038/leu.2008.3

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