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& ~+ w8 w8 T7 i$ s) N5 ?doi:10.1158/0008-5472.CAN-13-3012
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5-lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia
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# F/ E Z. \9 n$ @Jessica Roos1, Claudia Oancea1, Maria Heinssmann1, Dilawar Khan1, Hannelore Held1, Astrid S. Kahnt2, Ricardo Capelo2, Estel la Buscato2, Ewgenij Proschak2, Elena Puccetti3, Dieter Steinhilber2, Ingrid Fleming4, Thorsten J. Maier5, and Martin Ruthardt1,*+ y7 Y9 H; \* e5 U c& L7 l2 R
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1 w9 y5 F" x& j- v0 P0 o5 z3 qNon-steroidal anti-inflammatory drugs such as sulindac inhibit Wnt-signaling, which is critical to maintain cancer stem-cell like cells (CSC), but they also suppress the activity of 5-lipoxygenase (5-LO) at clinically feasible concentrations. Recently, 5-LO was shown to be critical to maintain CSC in a model of chronic myeloid leukemia. For these reasons, we hypothesized that 5-LO may offer a therapeutic target to improve the management of acute myeloid leukemia (AML), an aggressive disease driven by CSC. Pharmacological and genetic approaches were used to evaluate the effects of 5-LO blockade in a PML/RARα -positive model of AML. As CSC models we used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPC), which were retrovirally transduced with PML/RARα. We found that pharmacological inhibition of 5-LO interfered strongly with the aberrant stem cell capacity of PML/RARα-expressing HSPC. Through small molecule inhibitor studies and genetic disruption of 5-LO, we also found that Wnt and CSC inhibition is mediated by the enzymatically inactive form of 5-LO which hinders nuclear translocation of ß-catenin. Overall, our findings revealed that 5-LO inhibitors also inhibit Wnt signaling, not due to the interruption of 5-LO-mediated lipid signaling but rather to the generation of a catalytically inactive form of 5-LO which assumes a new function. Given the evidence that CSC mediate AML relapse after remission, eradication of CSC in this setting by 5-LO inhibition may offer a new clinical approach for immediate evaluation in AML patients. . _. s; H x, }! _) _% q1 r' L9 v( O
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