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https://hdl.handle.net/2440/58297
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Type: | Journal article |
Title: | Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors |
Author: | Hiwase, D. White, D. Powell, J. Saunders, V. Zrim, S. Frede, A. Guthridge, M. Lopez, A. D'Andrea, R. To, L. Vaz de Melo, J. Kumar, S. Hughes, T. |
Citation: | Leukemia, 2010; 24(4):771-778 |
Publisher: | Nature Publishing Group |
Issue Date: | 2010 |
ISSN: | 0887-6924 1476-5551 |
Statement of Responsibility: | 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. |
DOI: | 10.1038/leu.2009.299 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.1038/leu.2009.299 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
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