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Chronic Myeloproliferative Disorders

Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors

Abstract

The therapeutic success of imatinib in chronic myeloid leukemia (CML) is hampered by persistence of malignant stem cells. We investigated whether nilotinib, a more potent BCR-ABL kinase inhibitor could target CML primitive progenitors more effectively than imatinib. CML and normal progenitor cells were cultured with nilotinib or imatinib in growth factor supplemented medium. Nilotinib inhibited BCR-ABL kinase activity at lower concentrations than imatinib. Nilotinib inhibited mitogen-activated protein kinase (MAPK), AKT and STAT5 phosphorylation in CML CD34+ cells in the absence of growth factors (GFs), but did not suppress AKT and STAT5 activity, and resulted in increased MAPK activity, in the presence of GFs. Nilotinib and imatinib resulted in similar suppression of CML primitive and committed progenitors in long-term culture-initiating cell and colony-forming cell assays. Inhibition of progenitor growth was related to marked reduction in proliferation, but only a modest increase in apoptosis. Nilotinib did not show increased efficacy in reducing nondividing CML progenitors compared with imatinib. These results indicate that more potent tyrosine kinase inhibitors by themselves will not be more effective in eliminating CML progenitors than imatinib and that additional mechanism required for maintenance of malignant stem cells need to be identified to improve targeting of leukemia stem cells.

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Acknowledgements

We acknowledge the excellent technical support of Lucy Brown, Claudio Spalla and Alex Spalla from the Analytical Cytometry Core and Dr Marilyn Slovak and Victoria Bedell in the Cytogenetics Core laboratory for performing the FISH analysis. We acknowledge StemCyte for their generous gift of cord blood samples for these studies. This work was supported by NIH Grants R01 CA95684 to Ravi Bhatia. Ravi Bhatia is a Scholar at Clinical Research of the Leukemia and Lymphoma Society.

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Correspondence to R Bhatia.

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The whole work was performed in the City of Hope National Medical Center.

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Konig, H., Holtz, M., Modi, H. et al. Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors. Leukemia 22, 748–755 (2008). https://doi.org/10.1038/sj.leu.2405086

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