NPM1-Mutated Acute Myeloid Leukemia: Recent Developments and Open Questions.

IF 3.5 4区 医学 Q3 CELL BIOLOGY Pathobiology Pub Date : 2024-01-01 Epub Date: 2023-03-21 DOI:10.1159/000530253
Sanjay S Patel
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Abstract

Somatic mutations in the nucleophosmin (NPM1) gene occur in approximately 30% of de novo acute myeloid leukemias (AMLs) and are relatively enriched in normal karyotype AMLs. Earlier World Health Organization (WHO) classification schema recognized NPM1-mutated AMLs as a unique subtype of AML, while the latest WHO and International Consensus Classification (ICC) now consider NPM1 mutations as AML-defining, albeit at different blast count thresholds. NPM1 mutational load correlates closely with disease status, particularly in the post-therapy setting, and therefore high sensitivity-based methods for detection of the mutant allele have proven useful for minimal/measurable residual disease (MRD) monitoring. MRD status has been conventionally measured by either multiparameter flow cytometry (MFC) and/or molecular diagnostic techniques, although recent data suggest that MFC data may be potentially more challenging to interpret in this AML subtype. Of note, MRD status does not predict patient outcome in all cases, and therefore a deeper understanding of the biological significance of MRD may be required. Recent studies have confirmed that NPM1-mutated cells rely on overexpression of HOX/MEIS1, which is dependent on the presence of the aberrant cytoplasmic localization of mutant NPM1 protein (NPM1c); this biology may explain the promising response to novel agents, including menin inhibitors and second-generation XPO1 inhibitors. In this review, these and other recent developments around NPM1-mutated AML, in addition to open questions warranting further investigation, will be discussed.

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NPM1突变急性髓性白血病:最新进展与未决问题。
在新发急性髓性白血病(AML)中,约有 30% 的急性髓性白血病(AML)会出现核嗜蛋白(NPM1)基因的体细胞突变,而正常核型(NK)急性髓性白血病(AML)中的突变相对较多。世界卫生组织(WHO)早期的分类模式将NPM1突变的急性髓细胞白血病视为急性髓细胞白血病的一个独特亚型,而最新的WHO和国际共识分类(ICC)现在则将NPM1突变视为急性髓细胞白血病的定义,尽管囊胚数阈值不同。NPM1 突变负荷与疾病状态密切相关,尤其是在治疗后的情况下,因此,基于高灵敏度的突变等位基因检测方法已被证明可用于最小/可测量残留疾病(MRD)监测。MRD状态传统上是通过多参数流式细胞术(MFC)和/或分子诊断技术来测量的,但最近的数据表明,在这种急性髓细胞性白血病亚型中,MFC数据的解释可能更具挑战性。值得注意的是,MRD 状态并不能预测所有病例的患者预后,因此可能需要更深入地了解 MRD 的生物学意义。最近的研究证实,NPM1突变细胞依赖于HOX/MEIS1的过度表达,而HOX/MEIS1的过度表达又依赖于突变NPM1蛋白(NPM1c)的异常胞质定位;这种生物学特性可能解释了为什么新型药物(包括menin抑制剂和第二代XPO1抑制剂)会产生良好的反应。在这篇综述中,除了需要进一步研究的开放性问题外,还将讨论这些问题和其他有关 NPM1 突变急性髓细胞性白血病的最新进展。
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来源期刊
Pathobiology
Pathobiology 医学-病理学
CiteScore
8.50
自引率
0.00%
发文量
47
审稿时长
>12 weeks
期刊介绍: ''Pathobiology'' offers a valuable platform for the publication of high-quality original research into the mechanisms underlying human disease. Aiming to serve as a bridge between basic biomedical research and clinical medicine, the journal welcomes articles from scientific areas such as pathology, oncology, anatomy, virology, internal medicine, surgery, cell and molecular biology, and immunology. Published bimonthly, ''Pathobiology'' features original research papers and reviews on translational research. The journal offers the possibility to publish proceedings of meetings dedicated to one particular topic.
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