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Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/4515

Title: Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells
Authors: Bellodi, Cristian
Lidonnici, Maria Rosa
Hamilton, Ashley
Helgason, G. Vignir
Soliera, Angela Rachele
Ronchetti, Mattia
Galavotti, Sara
Young, Kenneth W.
Selmi, Tommaso
Yacobi, Rinat
Van Etten, Richard A.
Donato, Nick
Hunter, Ann
Dinsdale, David
Tirrò, Elena
Vigneri, Paolo
Nicotera, Pierluigi
Dyer, Martin J.S.
Holyoake, Tessa
Salomoni, Paolo
Calabretta, Bruno
Issue Date: 1-May-2009
Publisher: American Society for Clinical Investigation
Citation: Journal of Clinical Investigation, 2009, 119 (5), pp. 1109-1123.
Abstract: Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.
ISSN: 0021-9738
Links: http://dx.doi.org/10.1172/JCI35660
http://hdl.handle.net/2381/4515
Type: Article
Description: This is the author's final draft of the paper published as Journal of Clinical Investigation, 2009, 119 (5), pp. 1109-1123. The final version is available from http://www.jci.org/articles/view/35660. Doi: 10.1172/JCI35660
Appears in Collections:Published Articles, MRC Toxicology Unit

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