A Comprehensive Genomic Analysis of Nucleophosmin (NPM1) in Acute Myeloid Leukemia

<b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> Among 4206 cases, 633 (15.1%) featured <i>NPM1</i> GA, 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 included <i>DNMT3A</i> (39.2% vs. 12.6%; <i>p</i> < 0.0001), PTPN11 (18.3% vs. 7.5%; <i>p</i> < 0.0001), <i>FLT3</i> (54.5% vs. 14.7%; <i>p</i> < 0.0001), <i>IDH1</i> (16.1% vs. 5.6%; <i>p</i> < 0.0001), <i>IDH2</i> (19.0% vs. 9.0%; <i>p</i> < 0.0001), TET2 (23.4% vs. 13.5%; <i>p</i> < 0.0001), and <i>WT1</i> (12.5% vs. 9.4%; <i>p</i> = 0.02). GA was more frequent in NPM1wt AML and included <i>ASXL1</i> (17.1% vs. 3.6%; <i>p</i> 0.0001), <i>BCOR</i> (7.5% vs. 1.6%; <i>p</i> < 0.0001), <i>KMT2A</i> (14.7% vs. 0.2%; <i>p</i> < 0.0001), <i>RUNX1</i> (22.5% vs. 1.9%; <i>p</i> 0.0001), <i>STAG2</i> (6.9% vs. 1.6%; <i>p</i> < 0.0001) and <i>TP53</i> (19.1% vs. 4.1%; <i>p</i> < 0.0001). <b>Conclusions:</b> Mutations linked to therapy targets in AML, such as (<i>FLT3</i> and <i>IDH1/2</i>), <i>PTPN11</i>, and <i>DNMT3A</i> (both associated with inferior outcomes), are more commonly observed in NPM1mut AML, whereas <i>KMT2A</i>, <i>TP53</i>, and myelodysplastic-related mutations are more commonly observed in NPM1wt AML.