Background/Objectives:This study investigates genomic alterations (GA) between NPM1-mutated (NPM1mut) and wild-type (NPM1wt) acute myeloid leukemia (AML), aiming to better understand the AML genomic profile. NPM1mut AML represents a distinct clinical AML subtype with high relapse rates despite initial responsiveness to chemotherapy.Methods:A total of 4206 AML cases from 2019 to 2024 were analyzed using the FoundationOne Heme assay, incorporating comprehensive DNA and RNA sequencing. Patients were stratified into NPM1mut and NPM1wt cohorts, and genomic differences were systematically compared between the two groups.Results:Among 4206 cases, 633 (15.1%) featuredNPM1GA, with over 99% exhibiting short variant mutations. NPM1mut AML was more common in females (53.4% vs. 41.5%) and associated with a slightly higher median age (62 vs. 60 years). GA was more frequent in NPM1mut AML compared to the NPM1wt and includedDNMT3A(39.2% vs. 12.6%;p< 0.0001), PTPN11 (18.3% vs. 7.5%;p< 0.0001),FLT3(54.5% vs. 14.7%;p< 0.0001),IDH1(16.1% vs. 5.6%;p< 0.0001),IDH2(19.0% vs. 9.0%;p< 0.0001), TET2 (23.4% vs. 13.5%;p< 0.0001), andWT1(12.5% vs. 9.4%;p= 0.02). GA was more frequent in NPM1wt AML and includedASXL1(17.1% vs. 3.6%;p0.0001),BCOR(7.5% vs. 1.6%;p< 0.0001),KMT2A(14.7% vs. 0.2%;p< 0.0001),RUNX1(22.5% vs. 1.9%;p0.0001),STAG2(6.9% vs. 1.6%;p< 0.0001) andTP53(19.1% vs. 4.1%;p< 0.0001).Conclusions:Mutations linked to therapy targets in AML, such as (FLT3andIDH1/2),PTPN11, andDNMT3A(both associated with inferior outcomes), are more commonly observed in NPM1mut AML, whereasKMT2A,TP53, and myelodysplastic-related mutations are more commonly observed in NPM1wt AML.
背景/目的：本研究旨在探究NPM1突变型（NPM1mut）与野生型（NPM1wt）急性髓系白血病（AML）之间的基因组变异（GA），以更深入地理解AML的基因组特征。NPM1mut AML是一种独特的临床亚型，尽管对化疗初始反应良好，但具有较高的复发率。 方法：采用FoundationOne Heme检测平台，对2019年至2024年间的4206例AML病例进行了全面的DNA和RNA测序分析。将患者分为NPM1mut和NPM1wt两组，并系统比较了两组间的基因组差异。 结果：在4206例病例中，633例（15.1%）存在NPM1基因组变异，其中超过99%为短变异突变。NPM1mut AML在女性中更为常见（53.4% vs. 41.5%），且中位年龄略高（62岁 vs. 60岁）。与NPM1wt组相比，NPM1mut组中某些基因组变异的发生率更高，包括DNMT3A（39.2% vs. 12.6%；p < 0.0001）、PTPN11（18.3% vs. 7.5%；p < 0.0001）、FLT3（54.5% vs. 14.7%；p < 0.0001）、IDH1（16.1% vs. 5.6%；p < 0.0001）、IDH2（19.0% vs. 9.0%；p < 0.0001）、TET2（23.4% vs. 13.5%；p < 0.0001）和WT1（12.5% vs. 9.4%；p = 0.02）。而NPM1wt组中发生率更高的基因组变异包括ASXL1（17.1% vs. 3.6%；p < 0.0001）、BCOR（7.5% vs. 1.6%；p < 0.0001）、KMT2A（14.7% vs. 0.2%；p < 0.0001）、RUNX1（22.5% vs. 1.9%；p < 0.0001）、STAG2（6.9% vs. 1.6%；p < 0.0001）和TP53（19.1% vs. 4.1%；p < 0.0001）。 结论：与AML治疗靶点相关的突变，如FLT3、IDH1/2、PTPN11以及DNMT3A（后两者均与不良预后相关），在NPM1mut AML中更为常见；而KMT2A、TP53及骨髓增生异常相关突变则在NPM1wt AML中更常观察到。
A Comprehensive Genomic Analysis of Nucleophosmin (NPM1) in Acute Myeloid Leukemia
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