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

Devendra Hiwase, Deborah White, Jason A Powell, Verity Saunders, Stephanie Zrim, Amity Frede, Mark Andrew Guthridge, Angel F Lopez, Richard J D'Andrea, LuenBik To, Junia V Melo, Sharad Kumar, Timothy P Hughes

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44 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)771 - 778
Number of pages8
JournalLeukemia
Volume24
Issue number4
DOIs
Publication statusPublished - 2010
Externally publishedYes

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