Nucleophosmin (NPM1) mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the NPM1 mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES), at the bases of exportin-1(XPO1)-mediated aberrant cytoplasmic NPM1. Immunohistochemistry (IHC) detects cytoplasmic NPM1 and is predictive of the molecular alteration. Besides IHC and molecular sequencing, Western blotting (WB) with anti-NPM1 mutant specific antibodies is another approach to identify NPM1-mutated AML. Here, we show that among 382 AML cases with NPM1 exon 12 mutations, one was not recognized by WB, and describe the discovery of a novel combination of two mutations involving exon 12. This appeared as a conventional mutation A with the known TCTG nucleotides insertion/duplication accompanied by a second event (i.e., an 8-nucleotide deletion occurring 15 nucleotides downstream of the TCTG insertion), resulting in a new C-terminal protein sequence. Strikingly, the sequence included a functional NES ensuring cytoplasmic relocation of the new mutant supporting the role of cytoplasmic NPM1 as critical in AML leukemogenesis.

中文翻译：

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一种新奇的核磷蛋白 (NPM1) 基因突变组合导致急性髓性白血病 (AML) 中 NPM1 异常细胞质错位

发生在急性髓性白血病 (AML) 中的核磷蛋白 (NPM1)突变（目前已确定约 50 个）几乎完全聚集在外显子 12 中，并导致NPM1突变体 C 末端的常见变化，即色氨酸 288 和 290（或 290单独）并在 exportin-1（XPO1）介导的异常细胞质NPM1的基础上产生新的核输出信号（NES） 。免疫组织化学 (IHC) 检测细胞质NPM1并预测分子改变。除了 IHC 和分子测序，使用抗NPM1突变特异性抗体的蛋白质印迹 (WB)是另一种鉴定NPM1突变 AML 的方法。在这里，我们展示了在 382 例NPM1的 AML 病例中外显子 12 突变，其中一个未被 WB 识别，并描述了涉及外显子 12 的两个突变的新组合的发现。这表现为带有已知 TCTG 核苷酸插入/复制的常规突变 A，并伴有第二个事件（即在 TCTG 插入下游 15 个核苷酸处发生 8 个核苷酸缺失），产生一个新的 C 末端蛋白质序列。引人注目的是，该序列包括一个功能性 NES，确保新突变体的细胞质重新定位，支持细胞质NPM1在 AML 白血病发生中的作用。