High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia

Priscilla Wander, Susan T.C.J.M. Arentsen-Peters, Sandra S. Pinhanҫos, Bianca Koopmans, M. Emmy M. Dolman, Rijndert Ariese, Frank L. Bos, Patricia Garrido Castro, Luke Jones, Pauline Schneider, Miriam Guillen Navarro, Jan J. Molenaar, Anne C. Rios, C. Michel Zwaan, Ronald W. Stam*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Pediatric MLL-rearranged acute myeloid leukemia (AML) has a generally unfavorable outcome, primarily due to relapse and drug resistance. To overcome these difficulties, new therapeutic agents are urgently needed. Yet, implementing novel drugs for clinical use is a time-consuming, laborious, costly and high-risk process. Therefore, we applied a drug-repositioning strategy by screening drug libraries, comprised of >4000 compounds that are mostly FDA-approved, in a high-throughput format on primary MLL-rearranged AML cells. Here we identified pyrvinium pamoate (pyrvinium) as a novel candidate drug effective against MLL-rearranged AML, eliminating all cell viability at <1000 nM. Additional screening of identified drug hits on non-leukemic bone marrow samples, resulted in a decrease in cell viability of ∼50% at 1000 nM pyrvinium, suggesting a therapeutic window for targeting leukemic cells specifically. Validation of pyrvinium on an extensive panel of AML cell lines and primary AML samples showed comparable viabilities as the drug screen data, with pyrvinium achieving IC50 values of <80 nM in these samples. Remarkably, pyrvinium also induced cell toxicity in primary MLL-AF10+ AML cells, an MLL-rearrangement associated with a poor outcome. While pyrvinium is able to inhibit the Wnt pathway in other diseases, this unlikely explains the efficacy we observed as β-catenin was not expressed in the AML cells tested. Rather, we show that pyrvinium co-localized with the mitochondrial stain in cells, and hence may act by inhibiting mitochondrial respiration. Overall, this study shows that pyrvinium is highly effective against MLL-rearranged AML in vitro, and therefore represents a novel potential candidate for further studies in MLL-rearranged AML.

Original languageEnglish
Article number101048
JournalTranslational Oncology
Issue number5
Publication statusPublished - May 2021

Bibliographical note

Funding Information:
This work was financially supported by the KiKa Foundation. The KiKa Foundation had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

Publisher Copyright: © 2021


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