Genomic and Immunogenomic Profiling of Extramedullary Acute Myeloid Leukemia Reveals Actionable Clonal Branching and Frequent Immune Editing

Abstract

Extramedullary acute myeloid leukemia (eAML) is a rare form of myeloid neoplasm characterized by leukemic infiltration outside the bone marrow (BM). Despite its prognostic significance, eAML is often underdiagnosed and poorly characterized at molecular level. We performed a comprehensive genomic and immunogenomic profiling on paired BM and extramedullary specimens from 26 eAML patients, alongside over 400 AML cases without extramedullary involvement and 97 healthy controls. Clonal branching from BM was observed in 38.5% of extramedullary sites, frequently involving actionable mutations in FLT3, IDH2 and NPM1 genes. Both compartments were enriched in RAS pathway mutations and class II HLA losses, suggesting active immunoediting mechanisms driving eAML development. Strikingly all relapsed cases acquired FLT3 aberrations, highlighting therapeutic opportunities. These findings underpin the need for improved detection and routine genomic profiling, including targeted sequencing of suspected extramedullary lesions.