The Ohio State University Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH;
Blood. 2013 Nov 28;122(23):3778-83. doi: 10.1182/blood-2013-06-507426. Epub 2013 Oct 1.
The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of Mll(PTD/wt) and Flt3(ITD/wt) mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.
MLL 部分串联重复（PTD）和 FLT3 内部串联重复（ITD）突变的共表达与核型正常的急性髓系白血病（AML）的不良预后相关。在小鼠中，Mll(PTD/wt)和 Flt3(ITD/wt)突变的双敲入（dKI）诱导自发 AML，同时增加 DNA 甲基转移酶（Dnmt1、3a 和 3b）和全基因组 DNA 甲基化指数，从而再现其人类 AML 对应物。我们确定，Dnmts 的调节剂 miR-29b 在 dKI AML 小鼠的骨髓中下调。硼替佐米在体外 AML blasts 中表现出剂量依赖性增加 miR-29b 的表达，随后减少 Dnmts、降低增殖并增加凋亡。在体内，硼替佐米对 dKI AML 没有活性，但作为单一药物的脂质体包裹硼替佐米逆转了体内 miR-29b 的下调，并在开始治疗时具有高白血病负担的 80%的 dKI AML 小鼠中诱导了 90 天的无病缓解，而在尸检时没有复发的迹象。总之，这些数据支持脂质体硼替佐米作为单一药物可根除 Mll(PTD/wt):Flt3(ITD/wt) AML 在小鼠中，并且可能代表一种强大且有潜在治愈作用的高危人类疾病的方法。
