NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function.
NUP98-PHF23 is a chromatin-modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function.
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DOI：
10.1158/2159-8290.cd-13-0419
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发表时间：
2014-05
期刊：
影响因子：
28.2
通讯作者：
Aplan PD
中科院分区：
文献类型：
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作者：
Gough SM;Lee F;Yang F;Walker RL;Zhu YJ;Pineda M;Onozawa M;Chung YJ;Bilke S;Wagner EK;Denu JM;Ning Y;Xu B;Wang GG;Meltzer PS;Aplan PD
在本报告中，我们表明，与人类急性髓系白血病 (AML) 相关的 NUP98-PHF23 (NP23) 融合蛋白的表达会导致小鼠的髓系、红系、T 细胞和 B 细胞白血病。白血病和白血病前期组织表现出类似干细胞的表达特征，包括 Hoxa、Hoxb 和 Meis1 基因。已知 PHF23 PHD 结构域可结合 H3K4me3 残基，染色质免疫沉淀实验证明 NP23 蛋白在 H3K4me3 位点的特定子集（包括 Hoxa、Hoxb 和 Meis1）处结合染色质。用双硫仑处理 NP23 细胞，双硫仑抑制 PHD 结构域与 H3K4me3 残基的结合，快速、选择性地杀死 NP23 成髓细胞；细胞死亡之前 Hoxa、Hoxb 和 Meis1 的表达降低。此外，由相关融合基因 NUP98-JARID1A (NJL) 驱动的 AML 也对双硫仑敏感。因此，NP23 小鼠提供了一个平台来评估破坏致癌 PHD 蛋白与 H3K4me3 结合的化合物。
In this report, we show that expression of a NUP98-PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and pre-leukemic tissues display a stem cell-like expression signature including Hoxa, Hoxb, and Meis1 genes. The PHF23 PHD domain is known to bind H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein bound chromatin at a specific subset of H3K4me3 sites, including Hoxa, Hoxb, and Meis1. Treatment of NP23 cells with disulfiram, which inhibits the binding of PHD domains to H3K4me3 residues, rapidly and selectively killed NP23 myeloblasts; cell death was preceded by decreased expression of Hoxa, Hoxb, and Meis1. Furthermore, AML driven by a related fusion gene, NUP98-JARID1A (NJL), was also sensitive to disulfiram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3.