Chen Weina, Rassidakis Georgios Z, Medeiros L Jeffrey
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 72, Houston, TX 77030, USA.
Arch Pathol Lab Med. 2006 Nov;130(11):1687-92. doi: 10.5858/2006-130-1687-NGMIAM.
Heterozygous mutation of the nucleophosmin gene (NPM1) has recently been described as one of the most frequent genetic lesions in acute myeloid leukemia (AML).
(1) To discuss the clinical, morphologic, immunophenotypic, and genetic features of AML with NPM1 gene mutations, along with various detection methods, (2) To explore the mechanisms by which NPM1 gene mutations contribute to leukemogenesis. DATA SOURCES/EXTRACTION: Data were analyzed from 7 recently published papers.
NPM1 gene mutations tend to occur more frequently in women, and also tend to be associated with a higher white blood cell count. There is no significant age difference. NPM1-mutated AML is preferentially associated with AML with monocytic differentiation (in particular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations, and a trend toward favorable clinical outcome, especially in patients without FLT3 gene mutation. NPM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM. Several methods are suitable for detecting NPM1 gene mutation, including molecular and immunohistochemical studies. These mutations may contribute to leukemogenesis, at least in part, through disruption of the p14(ARF) (alternative reading frame) MDM2-p53 pathway and centrosomal duplication.
Detection of NPM1 gene mutations may allow dissection of the heterogeneous group of AML with normal karyotype into prognostically different subgroups. Exploring the mechanisms may lead to a better understanding of how mutant NPM protein becomes leukemogenic, thereby providing insights for the development of new chemotherapeutic agents.
核磷蛋白基因（NPM1）的杂合突变最近被描述为急性髓系白血病（AML）中最常见的基因病变之一。
（1）讨论伴有NPM1基因突变的AML的临床、形态学、免疫表型和遗传学特征，以及各种检测方法；（2）探讨NPM1基因突变导致白血病发生的机制。数据来源/提取：分析了最近发表的7篇论文的数据。
NPM1基因突变在女性中更易发生，也往往与较高的白细胞计数相关。年龄差异不显著。NPM1突变的AML优先与单核细胞分化的AML（特别是FAB M5b）、缺乏CD34、正常细胞遗传学、FLT3基因突变相关，并且有临床预后良好的趋势，尤其是在没有FLT3基因突变的患者中。NPM1基因突变导致第12外显子C末端的移码，破坏NPM核仁定位信号或产生富含亮氨酸的核输出基序，导致NPM在细胞质中异常积累。有几种方法适用于检测NPM1基因突变，包括分子和免疫组织化学研究。这些突变可能至少部分通过破坏p14（ARF）（可变阅读框）MDM2-p53途径和中心体复制而导致白血病发生。
检测NPM1基因突变可能有助于将核型正常的异质性AML组分为预后不同的亚组。探索其机制可能有助于更好地理解突变的NPM蛋白如何导致白血病，从而为开发新的化疗药物提供思路。
