Multiomic characterization, early detection, and therapeutic targeting of myeloid sarcoma
Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in ∼10% of patients, and has not yet been included in large-scale genomic studies. The critical biological changes that drive tumor evolution are unknown, its detection in asymptomatic patients remains a clinical challenge, and treatment options are limited as patients are often excluded from clinical trials, rendering it a neglected disease entity. Based on comprehensive multi-omic profiling, we demonstrate that myeloid sarcoma evolves from medullary AML with distinct sitespecific clonal evolution patterns. Additionally, we show that circulating tumor DNA sequencing can serve as a non-invasive method for molecular profiling of myeloid sarcoma, offering a novel avenue in molecular diagnostics. We characterize unique transcriptional profiles of myeloid sarcoma, reflecting immune evasion and adaptation to an extramedullary microenvironment. We provide evidence for a key role of RAS pathway activation and demonstrate in murine models of myeloid sarcoma that RAS inhibition effectively reduces tumor burden. Overall, our data highlight key differences between medullary AML and myeloid sarcoma including universal molecular evolution and RAS pathway activation as hallmarks of the disease and nominate RAS inhibition as a promising therapeutic strategy for patients with myeloid sarcoma.
Authors
- Hager Mansour
- Zihai Li (ORCID: https://orcid.org/0000-0003-4603-927X)
- María Guillamot (ORCID: https://orcid.org/0000-0001-6970-5250)
- Alice S. Mims (ORCID: https://orcid.org/0000-0002-8971-2199)
- Benjamin Kelly (ORCID: https://orcid.org/0000-0002-7796-3994)
- Wafa Al-Santli (ORCID: https://orcid.org/0009-0001-6332-8789)
- Daniel A. Pollyea (ORCID: https://orcid.org/0000-0001-6519-4860)
- Ravi K. Patel (ORCID: https://orcid.org/0000-0001-5203-899X)
- Luis Chiriboga (ORCID: https://orcid.org/0000-0002-2028-6873)
- Aristotelis Tsirigos (ORCID: https://orcid.org/0000-0002-7512-8477)
- Maria Velegraki (ORCID: https://orcid.org/0000-0003-3062-9777)
- Elaine R. Mardis (ORCID: https://orcid.org/0000-0002-5892-1553)
- Isaiah Boateng
- Bettina Nadorp (ORCID: https://orcid.org/0000-0003-1974-8425)
- Sanam Loghavi (ORCID: https://orcid.org/0000-0001-8980-3202)
- Lynne V. Abruzzo (ORCID: https://orcid.org/0000-0001-6113-7447)
- Andrea Laganson (ORCID: https://orcid.org/0009-0002-9128-7598)
- Tejas Patel (ORCID: https://orcid.org/0000-0002-8766-5632)
- Eirini P. Papapetrou (ORCID: https://orcid.org/0000-0001-7002-417X)
- Adrienne Heyrosa
- Christine M. McMahon (ORCID: https://orcid.org/0000-0001-9745-9595)
- Jill Buss
- Zoe Ciantra
- Alan H. Shih (ORCID: https://orcid.org/0000-0003-4618-9673)
- Linda Procell
- Saranga Wijeratne (ORCID: https://orcid.org/0000-0002-9782-4406)
- John Byrd
- Ross Levine
- Benjamin Harris Kaffenberger (ORCID: https://orcid.org/0000-0001-8079-0011)
- Audrey Lasry (ORCID: https://orcid.org/0000-0001-6588-6760)
- Iannis Aifantis (ORCID: https://orcid.org/0000-0001-6857-1035)
- Rebecca Austin (ORCID: https://orcid.org/0009-0007-2807-7025)
- Arwa Shana’ah
- Christopher J. Walker (ORCID: https://orcid.org/0000-0001-8732-4777)
- Ann-Kathrin Eisfeld
- Hasan Abaza
- Helee Desai
Institutions
- Nationwide Children's Hospital (US)
- University of Colorado System (US)
- Kettering University (US)
- Immune Regulation (United Kingdom) (GB)
- Indiana University School of Medicine
- The Ohio State University (US)
- New York University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-05
- DOI
- https://doi.org/10.64898/2025.12.04.689069
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00