RAS pathway activation and microenvironmental adaptation as hallmarks of myeloid sarcoma

Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in up to 20% of patients, and remains strikingly understudied in large-scale genomic and multiomic investigations. The key biological drivers of its tumor evolution are largely unknown; timely detection in asymptomatic patients poses a clinical challenge, and effective treatment options are limited, as patients are often excluded from clinical trials, rendering it a largely neglected disease entity. Here, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution patterns. This is supported by unique transcriptional signatures of myeloid sarcoma that reflect adaptation to the extramedullary microenvironment. Also, we establish a proof of concept that circulating tumor DNA sequencing can capture the molecular composition of myeloid sarcoma, offering a potential non-invasive approach for molecular profiling of extramedullary AML. Collectively, our findings highlight marked biologic differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as hallmarks of the disease.