Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development.
Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development.
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DOI：
10.18632/oncotarget.10878
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发表时间：
2016-08-23
期刊：
影响因子：
--
通讯作者：
Alcalay M
中科院分区：
文献类型：
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作者：
Barbieri E;Deflorian G;Pezzimenti F;Valli D;Saia M;Meani N;Gruszka AM;Alcalay M
核磷蛋白(NPM1)是一种普遍存在的多功能磷蛋白，具有致癌和抑瘤功能。NPM1基因突变是急性髓系白血病(AML)中最常见的基因改变，导致一种胞浆定位异常的突变蛋白NPMc+的表达。虽然NPMc+可在动物模型中引起骨髓增殖和急性髓系白血病，但其作用机制在很大程度上仍不清楚。在这里，我们报道了NPMc+在斑马鱼发育的早期阶段激活了典型的Wnt信号，并决定了原始造血过程中Wnt依赖的祖细胞数量的增加。一致地，在含有NPMc+的急性髓系白血病细胞中，规范的Wnt途径是活跃的，患者来源的OCI-AML3细胞系中突变蛋白的缺失导致活性β-catenin和Wnt靶基因水平的下降。我们的结果揭示了NPMc+的一种新功能，并为研究携带NPM1突变的AML的分子发病机制提供了线索。
Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis. Coherently, the canonical Wnt pathway is active in AML blasts bearing NPMc+ and depletion of the mutant protein in the patient derived OCI-AML3 cell line leads to a decrease in the levels of active β-catenin and of Wnt target genes. Our results reveal a novel function of NPMc+ and provide insight into the molecular pathogenesis of AML bearing NPM1 mutations.