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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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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DOI: https://doi.org/10.1038/leu.2008.3
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