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Chronic Myeloproliferative Neoplasias

Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors

Leukemia volume 24, pages 771–778 (2010)Cite this article

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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 (⩾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.

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Acknowledgements

The research was supported by the NHMRC grant.

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Authors and Affiliations

  1. Division of Haematology, SA Pathology, Adelaide, South Australia, Australia

    D K Hiwase, D L White, V A Saunders, S A Zrim, A K Frede, R J D'Andrea, L B To, J V Melo, S Kumar & T P Hughes

  2. Department of Medicine, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia

    D K Hiwase, D L White, M A Guthridge, A F Lopez, R J D'Andrea, L B To, J V Melo, S Kumar & T P Hughes

  3. Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia

    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 & T P Hughes

  4. Division of Human Immunology, SA Pathology, Adelaide, South Australia, Australia

    J A Powell, M A Guthridge & A F Lopez

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  1. D K Hiwase
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Correspondence to T P Hughes.

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Competing interests

Devendra K Hiwase, Jason A Powell, Verity A Saunders, Stephanie A Zrim, Amity K Frede, Mark A Guthridge, Richard J D’andrea, Luen Bik To, Junia V Melo and Sharad Kumar have no conflict of interest. Timothy Hughes and Deborah L White receive honoraria and research grants from Novartis and Bristol-Myers Squibb. Angel F Lopez receives honoraria and research grants from CSL.

Additional information

contribution: Devendra K Hiwase designed the experiments, analyzed the data and wrote the paper. Richard J D’Andrea, Mark A Guthridge, Angel F Lopez and Luen Bik To provided critical review of the paper. Deborah L White, Junia V Melo, Sharad Kumar and Timothy P Hughes helped in designing the experiments, analyzing the data and writing the paper. Jason A Powell, Verity A Saunders, Stephanie A Zrim and Amity Frede helped in performing the experiments.

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Hiwase, D., White, D., Powell, J. et al. Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors. Leukemia 24, 771–778 (2010). https://doi.org/10.1038/leu.2009.299

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