5-lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia

Roos, Jessica, Oancea, Claudia, Heinssmann, Maria, Khan, Dilawar, Held, Hannelore, Kahnt, Astrid S., Capelo, Ricardo, la Buscato, Estel, Proschak, Ewgenij, Puccetti, Elena, Steinhilber, Dieter, Fleming, Ingrid, Maier, Thorsten J. and Ruthardt, Martin ORCID: https://orcid.org/0000-0003-1021-3811 2014. 5-lipoxygenase is a candidate target for therapeutic management of stem cell-like cells in acute myeloid leukemia. Cancer Research 74 (18) , pp. 5244-5255. 10.1158/0008-5472.CAN-13-3012

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Abstract

Nonsteroidal 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 CSCs. Pharmacologic 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 pharmacologic inhibition of 5-LO interfered strongly with the aberrant stem cell capacity of PML/RARα-expressing HSPCs. 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 β-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 due to the generation of a catalytically inactive form of 5-LO, which assumes a new function. Given the evidence that CSCs mediate AML relapse after remission, eradication of CSCs in this setting by 5-LO inhibition may offer a new clinical approach for immediate evaluation in patients with AML

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	American Association for Cancer Research
ISSN:	0008-5472
Date of Acceptance:	21 June 2014
Last Modified:	31 Oct 2022 10:43
URI:	https://orca.cardiff.ac.uk/id/eprint/85886

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