RAS Pathway Activation and Microenvironmental Adaptation as Hallmarks of Myeloid Sarcoma

作者：Bettina Nadorp, Audrey Lasry, Sanam Loghavi, Ravi Patel, Hager Mansour, Pier Edoardo Rovatti, Benjamin J. Kelly, Christopher J. Walker, Jill Buss, Isaiah Boateng, Wafa Al-Santli, Zoe Ciantra, Rebecca Austin, Helee Desai, Hasan Abaza, Linda Procell, Tejas Patel, Bejamin Kaffenberger, Saranga Wijeratne, María Guillamot, Maria Velegraki, Luis A. Chiriboga, Zihai Li, Daniel A. Pollyea, Christine M. McMahon, Arwa Shana’ah, John C. Byrd, Manel Esteller, Eirini P. Papapetrou, Aristotelis Tsirigos, Alice S. Mims, Elaine R. Mardis, Iannis Aifantis, Ann-Kathrin Eisfeld · 发表于：Blood Cancer Discovery · 年份：2026 · DOI：10.1158/2643-3230.bcd-26-0160 · 被引用次数：1 · 研究领域：Acute Myeloid Leukemia Research、Immune cells in cancer、Chronic Myeloid Leukemia Treatments

Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in approximately 20% of patients and remains strikingly understudied in large-scale genomic and multiomic investigations. The key 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. In this study, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution. This is supported by unique transcriptional signatures of myeloid sarcoma, reflecting adaptation to the extramedullary microenvironment. We establish a proof of concept that circulating tumor DNA (ctDNA) sequencing captures the molecular composition of myeloid sarcoma, offering a potential noninvasive approach for molecular profiling of extramedullary AML. Our findings highlight marked differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as disease hallmarks. SIGNIFICANCE: We provide a comprehensive multiomic characterization of myeloid sarcoma, identifying key molecular pathways that contribute to its development, and suggest ctDNA as a noninvasive method of detection. We identify RAS pathway activation and transcriptional adaptation to the solid tissue microenvironment as cardinal features of ...