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|Title:||Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors|
Vaz de Melo, J.
|Citation:||Leukemia, 2010; 24(4):771-778|
|Publisher:||Nature Publishing Group|
|D. K. Hiwase, D. L. White, J. A. Powell, V. A. Saunders, S. A. Zrim, A. K. Frede, M. A. Guthridge, A. F. Lopez, R. J. D'Andrea, L. B. To, J. V. Melo, S. Kumar and T. P. Hughes|
|Abstract:||In chronic myeloid leukemia (CML) cell lines, brief exposure to pharmacologically relevant dasatinib concentrations results in apoptosis. In this study, we assess the impact of intensity and duration of Bcr-Abl kinase inhibition on primary CD34(+) progenitors of chronic phase CML patients. As CML cells exposed to dasatinib in vivo are in a cytokine-rich environment, we also assessed the effect of cytokines (six growth factors cocktail or granulocyte-macrophage colony-stimulating factor (CSF) or granulocyte-CSF) in combination with dasatinib. In the presence of cytokines, short-term intense Bcr-Abl kinase inhibition (>or=90% p-Crkl inhibition) with 100 nM dasatinib did not reduce CD34(+) colony-forming cells (CFCs). In contrast, without cytokines, short-term exposure to dasatinib reduced CML-CD34(+) CFCs by 70-80%. When cytokines were added immediately after short-term exposure to dasatinib, CML-CD34(+) cells remained viable, suggesting that oncogene dependence of these cells can be overcome by concomitant or subsequent exposure to cytokines. Additional inhibition of Janus tyrosine kinase (Jak) activity re-established the sensitivity of CML progenitors to intense Bcr-Abl kinase inhibition despite the presence of cytokines. These findings support the contention that therapeutic strategies combining intense Bcr-Abl kinase inhibition and blockade of cytokine signaling pathways can be effective for eradication of CML progenitors.|
|Keywords:||CML; cytokines; tyrosine kinase inhibitors|
|Rights:||© 2010 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.|
|Appears in Collections:||Medicine publications|
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