Fiskus W, Sharma S, Saha S, Shah B, Devaraj S G T, Sun B, Horrigan S, Leveque C, Zu Y, Iyer S, Bhalla K N
Houston Methodist Research Institute, Houston, TX, USA.
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Leukemia. 2015 Jun;29(6):1267-78. doi: 10.1038/leu.2014.340. Epub 2014 Dec 8.
The canonical wingless-type MMTV integration site (WNT)-β-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 β-catenin, causing increased nuclear translocation and co-factor activity of β-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 β-catenin levels. BC treatment disrupted the binding of β-catenin with the scaffold protein transducin β-like 1 and proteasomal degradation and decline in the nuclear levels of β-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 β-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.
经典的无翅型MMTV整合位点（WNT）-β-连环蛋白信号通路对于急性髓系白血病（AML）干细胞/原始祖细胞（BPCs）的自我更新、生长和存活至关重要。失调的WNT信号传导抑制β-连环蛋白的降解，导致AML BPCs中β-连环蛋白与转录调节因子T细胞因子（TCF）4/淋巴样增强因子1的核转位增加和辅因子活性增强。在此，我们确定了已知可降低β-连环蛋白水平的蒽醌肟类似物BC2059（BC）的临床前抗AML活性。BC处理破坏了β-连环蛋白与支架蛋白转导素β样1的结合以及蛋白酶体降解，并降低了β-连环蛋白的核水平。这与TCF4转录活性降低及其靶基因细胞周期蛋白D1、c-MYC和存活素的表达减少有关。BC处理剂量依赖性地诱导培养的和原发性AML BPCs凋亡。用BC治疗还显著提高了移植有培养的或原发性AML BPCs（其β-连环蛋白呈核表达）的免疫缺陷小鼠的中位生存期。与泛组蛋白去乙酰化酶抑制剂帕比司他联合治疗可协同诱导培养的和原发性AML BPCs凋亡，包括那些表达FLT3-ITD的细胞，并且进一步显著提高了移植有原发性AML BPCs的免疫缺陷小鼠的存活率。这些发现强调了BC有前景的临床前活性，并保证对其针对人类AML，尤其是那些表达FLT3-ITD的AML进行进一步测试。
