Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML
Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML
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DOI：
10.1182/blood-2005-11-4745
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发表时间：
2006-06-01
期刊：
影响因子：
20.3
通讯作者：
Nicoletti, Ildo
中科院分区：
文献类型：
--
作者：
Falini, Brunangelo;Bolli, Niccolò;Nicoletti, Ildo
我们最近发现异常的胞浆表达的nucleophosmin（NPM）作为免疫组化标记的一个大的亚组急性髓细胞白血病（AML）（约三分之一的成人AML），其特征是正常的核型和突变发生在外显子12的NPM基因。在本文中，我们阐明了NPM异常细胞质定位的分子机制。迄今为止鉴定的所有29个AML相关突变的NPM等位基因编码异常蛋白质，其在C末端获得核输出信号（内斯）基序，并丢失决定核仁定位的色氨酸残基288和290（或仅残基290）。我们第一次表明，这两个改变是至关重要的NPM突变出口从细胞核到细胞质。事实上，NPM的细胞质积累被阻断的leptomycin-B和ratjadones，特定的exportin-1/Crm 1-抑制剂，并通过重新插入色氨酸残基288和290，这分别重新定位NPM突变体在核质和核仁。NPM白血病突变体反过来将野生型NPM从核仁募集到核质和细胞质。这些发现表明，旨在将NPM重新靶向其生理位点的潜在治疗策略必须克服2个障碍，即新的内斯基序和NPM突变体C末端的突变色氨酸。
We recently identified aberrant cytoplasmic expression of nucleophosmin (NPM) as the immunohistochemical marker of a large subgroup of acute myeloid leukemia (AML) (about one-third of adult AML)that is characterized by normal karyotype and mutations occurring at the exon-12 of the NPM gene. In this paper, we have elucidated the molecular mechanism underlying the abnormal cytoplasmic localization of NPM. All 29 AML-associated mutated NPM alleles so far identified encode abnormal proteins which have acquired at the C-terminus a nuclear export signal (NES) motif and lost both tryptophan residues 288 and 290 (or only the residue 290) which determine nucleolar localization. We show for the first time that both alterations are crucial for NPM mutant export from nucleus to cytoplasm. In fact, the cytoplasmic accumulation of NPM is blocked by leptomycin-B and ratjadones, specific exportin-1/Crm1-inhibitors, and by reinsertion of tryptophan residues 288 and 290, which respectively relocate NPM mutants in the nucleoplasm and nucleoli. NPM leukemic mutants in turn recruit the wild-type NPM from nucleoli to nucleoplasm and cytoplasm. These findings indicate that potential therapeutic strategies aimed to retarget NPM to its physiological sites will have to overcome 2 obstacles, the new NES motif and the mutated tryptophan(s) at the NPM mutant C-terminus.