Abstract
The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) displays exclusive cytoplasmic localization and constitutive tyrosine kinase activity leading to the activation of different pathways that favor cell proliferation and survival. BCR-ABL induces survivin expression at both the mRNA and protein level, thus inhibiting the apoptotic machinery of CML cells and contributing to the expansion of the leukemic clone. We report that, in human CML cell lines, BCR-ABL-mediated upregulation of survivin involves the JAK2/STAT3 pathway since silencing of either protein caused a consistent reduction in survivin expression. Cell lines unresponsive to imatinib mesylate (IM) because of BCR-ABL gene amplification were not resensitized to the drug after survivin downregulation. However, cells insensitive to IM because of point mutations in the BCR-ABL kinase domain were highly responsive to hydroxyurea (HU) after survivin silencing. To address the possible clinical applications of our results, we used shepherdin, a cell-permeable peptidomimetic compound that downregulates survivin expression by preventing its interaction with Hsp90. Incubation with shepherdin of immortalized cell lines both sensitive and resistant to IM enhanced cell death induced by HU and doxorubicin. Similarly, the combination of shepherdin with first- and second-generation tyrosine kinase inhibitors reduced the colony-forming potential of human progenitors derived from both patients with IM-sensitive and IM-resistant CML. These results suggest that strategies aimed at reducing survivin levels may represent a potential therapeutic option for patients with CML unresponsive to IM.
Highlights
A reciprocal translocation between chromosomes 9 and 22 generates the abnormal Philadelphia (Ph) chromosome that, in turn, encodes for the chimaeric BCR-ABL oncogene [1]
We have previously reported that, in primary hematopoietic cells isolated from patients diagnosed with chronic myelogenous leukemia (CML), the amount of BCR-ABL transcript significantly correlates with the expression levels of survivin [14]
We found that STAT3C promoted an increase in survivin levels in all 4 CML cells tested, implying that the JAK2/STAT3 cascade is a major regulator of survivin expression in CML cells
Summary
A reciprocal translocation between chromosomes 9 and 22 generates the abnormal Philadelphia (Ph) chromosome that, in turn, encodes for the chimaeric BCR-ABL oncogene [1]. The ensuing BCR-ABL oncoprotein displays constitutive tyrosine kinase activity thereby activating multiple signaling pathways that lead to the development of chronic myeloid leukemia BCR-ABL– dependent activation of the phosphoinositide 3-kinase and the upregulation of Bcl-xL [3, 4] contribute to block cytochrome C release from the mitochondria and inhibit caspase activity, hampering the apoptotic machinery of CML cells and favoring the survival of leukemic myeloid progenitors. Treatment of CML cells with the ABL. Authors' Affiliation: Department of Clinical and Molecular Bio-Medicine, University of Catania, Catania, Italy.
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