Klag T.,Universitaotsklinikum Jena |
Hartel N.,University of Heidelberg |
Erben P.,University of Heidelberg |
Schwaab J.,University of Heidelberg |
And 4 more authors.
Leukemia | Year: 2012
Overcoming resistance against BCR-ABL-inhibitors in chronic myeloid leukemia (CML) is central to prevent progression to advanced phase disease. Kinase mutations of BCR-ABL and cytokine-mediated modulation of response to tyrosine kinase inhibitors (TKIs) are key mechanisms governing clinical response to imatinib and second generation TKIs. Omacetaxine mepesuccinate is effective in imatinib-resistant CML with reported stem cell activity. We specifically thought to explore omacetaxine in the context of the pan-resistant mutant T315I, and in its potential to modify cytokine-dependent resistance. Omacetaxine was investigated in cell lines and primary CD34+ enriched progenitor cells from patients with CML. Addition of cytokines, shown to revert the efficacy of TKIs in BCR-ABL-positive cells, does not affect omacetaxine mediated antiproliferative activity, neither in cell lines nor in primary CML CD34+ progenitor cells. Looking at potential mechanisms, we found marked downregulation of the common β-subunit c of the cytokine-receptors (cCRβc) for IL3, IL5 and GM-CSF by omacetaxine in cell lines and primary progenitor cultures. The observed cytokine-independent in-vitro cytotoxicity of omacetaxine may be explained by downregulation of cCRβc. Whether this can be used clinically as a means to optimize the stem cell activity of TKIs merits further evaluation. © 2012 Macmillan Publishers Limited. Source