Year: 2026
Type: article
Study design: Observational Study
Abstract: Background NPM1 mutations genetically define a frequent acute myeloid leukemia (AML) entity, representing 30% of adult AML cases, and marked by distinct clinical and prognostic features. NPM1-mutated AML is characterized by a high blast burden, elevated white blood cell (WBC) and platelet counts, and frequent extramedullary involvement. NPM1 mutations are often associated with normal cytogenetics and co-occur with mutations in DNA methylation genes, including DNMT3A, TET2, IDH1, and IDH2, and signaling pathway genes, including FLT3, NRAS, PTPN11, and KRAS. Although NPM1 mutations are generally associated with favorable prognosis, the impact of recurrent co-mutations, such as FLT3-ITD, DNMT3A, and IDH1/2, remains critical for refining prognostic classification and/or guiding therapeutic decisions. A key challenge in NPM1-mutated AML is understanding how co-occurring mutations modulate disease progression, prognostic classification, and clinical outcome. Aim This study aims to characterize the mutational landscape of NPM1-AML in a reference laboratory, focusing on co-mutation patterns and their association with clinical characteristics. The Research Ethics Committee at INCA approved the study. Results and Conclusion We analyzed samples from 66 NPM1-mutated adult AML patients, diagnosed and treated at four hematology centers in Rio de Janeiro. The median age at diagnosis was 53 years (18- 81), and 58.6% of patients were female. Median WBC and platelet counts were 28.9 × 10⁹/L (1.66–425.0 × 10⁹/L) and 40.0 × 10⁹/L (3.0–364.0 × 10⁹/L), respectively, and median blast percentage was 62.5%. A normal karyotype was observed in 83% (25/30) of patients. Most patients (71%; 35/49) received intensive induction chemotherapy, whereas 16% (8/49) were treated with low-intensity chemotherapy. Fifty-eight patients were screened for FLT3-ITD and DNMT3A mutations. FLT3-ITD and NPM1 mutations co-occurred in 48,3% patients (28/58). Of these, 46,4% (13/28) patients were triple-mutated, presenting the DNMT3A R882H (n=9) or R882C (n=4) mutations. Among FLT3 wild-type patients, 8 presented DNMT3A mutations: R882H (n=7) or R882C (n=1). Next-generation sequencing (NGS) using myeloid gene panels was performed in 16 patients, identifying NPM1 mutation isoforms and 49 additional genetic variants. As expected, the most frequent co-mutations detected were DNMT3A (18.4%) and FLT3 alterations (FLT3-ITD, 20.4%; FLT3-TKD, 8.2%), followed by IDH2 (10.2%), KRAS and PTPN11 (6.2% each), IDH1 (4.3%) and GATA2, WT1, RUNX1 and TET2 (2.0% each). Additionally, variants of unknown significance were observed in BRAF, GATA2, RAD21, SAMD9L and TET2. Although NPM1-mutated AML is recognized as an AML entity, it presents considerable molecular heterogeneity, characterized by subclonal diversity. These results are representative of the NPM1 AML biology: high blast burden, frequent normal karyotype, and enrichment for FLT3 and DNMT3A co-mutations. Identifying co-occurring genetic alterations may be relevant for disease management. For instance, the co-occurrence of DNMT3A, NPM1, and FLT3 mutations (triple-mutated AML) has been associated with inferior survival in previous studies. This study highlights the molecular heterogeneity of NPM1-mutated AML and reinforces the importance of integrating NGS into the clinical diagnosis to improve risk stratification and guide therapeutic decision-making.
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223128333