NPM1-rearranged AML: clinical features, molecular pathogenesis, and therapeutic perspectives

Nucleophosmin 1 (NPM1) gene aberrations are among the most common genetic alterations in acute myeloid leukemia (AML). NPM1 mutations (NPM1c), detected in 30-40% of adult AML cases, are well-characterized and associated with distinct clinical and molecular features. In contrast, NPM1 rearrangements (NPM1-r), involving rare fusion partners such as MLF1, CCDC28A, HAUS1, and RARA, are much less common and have historically been poorly understood. However, recent studies have begun to shed light on the molecular mechanisms and clinical characteristics of NPM1-r AML, revealing overlapping features with NPM1c-AML. Both types share key leukemogenic mechanisms, including cytoplasmic mislocalization of NPM1, interaction with XPO1, and sustained HOX gene expression, which drive leukemic transformation. NPM1-r AML may exhibit unique clinical characteristics, including a higher prevalence in younger patients and potentially a poorer prognosis, although further validation in larger cohorts is needed. Therapeutic strategies targeting XPO1 and Menin, which have shown promise in NPM1c-AML, may also hold potential for NPM1-r AML. Continued research is essential to further elucidate the biology of this rare AML subtype and to establish optimized treatment strategies.