RAS pathway activation and microenvironmental adaptation as hallmarks of myeloid sarcoma

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.