Journal
LEUKEMIA
Volume 29, Issue 6, Pages 1267-1278Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2014.340
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Funding
- National Institutes of Health, National Cancer Institute [R01 CA173877]
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The canonical wingless-type MMTV integration site (WNT)-beta-catenin pathway is essential for self-renewal, growth and survival of acute myeloid leukemia (AML) stem/blast progenitor cells (BPCs). Deregulated WNT signaling inhibits degradation of beta-catenin, causing increased nuclear translocation and co-factor activity of beta-catenin with the transcriptional regulator T-cell factor (TCF) 4/lymphoid enhancer factor 1 in AML BPCs. Here, we determined the pre-clinical anti-AML activity of the anthraquinone oxime-analog BC2059 (BC), known to attenuate beta-catenin levels. BC treatment disrupted the binding of beta-catenin with the scaffold protein transducin beta-like 1 and proteasomal degradation and decline in the nuclear levels of beta-catenin. This was associated with reduced transcriptional activity of TCF4 and expression of its target genes, cyclin D1, c-MYC and survivin. BC treatment dose-dependently induced apoptosis of cultured and primary AML BPCs. Treatment with BC also significantly improved the median survival of immune-depleted mice engrafted with either cultured or primary AML BPCs, exhibiting nuclear expression of beta-catenin. Co-treatment with the pan-histone deacetylase inhibitor panobinostat and BC synergistically induced apoptosis of cultured and primary AML BPCs, including those expressing FLT3-ITD, as well as further significantly improved the survival of immune-depleted mice engrafted with primary AML BPCs. These findings underscore the promising pre-clinical activity and warrant further testing of BC against human AML, especially those expressing FLT3-ITD.
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