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PLoS By Category | Recent PLoS Articles
Hematology - Molecular Biology - Oncology

Sulindac Sulfide Reverses Aberrant Self-Renewal of Progenitor Cells Induced by the AML-Associated Fusion Proteins PML/RARa and PLZF/RARa
Published: Tuesday, July 19, 2011
Author: Gunnar Steinert et al.

by Gunnar Steinert, Claudia Oancea, Jessica Roos, Heike Hagemeyer, Thorsten Maier, Martin Ruthardt, Elena Puccetti

Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARa, PLZF/RARa, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARa and PLZF/RARa or AML-1/ETO activate Wnt signaling by upregulating ?-catenin and ß-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARa-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both ß-catenin and ?-catenin in X-RARa-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARa-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARa, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings.
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