A tale of two sites - Distinct spatial differences between bone marrow and extramedullary AML.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and remains associated with poor overall survival. Beyond genetic factors in the bone marrow (BM) that drive clonal evolution, leukemic progression, immune evasion, and therapy resistance, far less is known about extramedullary (EM) AML, a clinically relevant manifestation characterized by leukemic infiltration of peripheral tissues and frequently associated with adverse outcomes. This review focuses on the spatial heterogeneity of AML, differentiating between BM and EM disease, elucidating how niche components shape leukemic behavior, clonal evolution, and treatment resistance. Furthermore, we review current clinical practice and evidence for the clinical approach, diagnostic management, and treatment of patients with EM AML. At last, we highlight the transformative role of spatial analysis platforms, enabling high-resolution mapping of niche cell and leukemic cell interactions and discuss their potential to improve diagnosis and personalized therapeutic strategies for EM AML.