MMRN1-EGFR drives sialylglycan-Siglec immune evasion in AML leukemia stem cells
- Cell Stem Cell. 2026 May 7;33(5):800-819.e9. doi: 10.1016/j.stem.2026.03.012.
- 1. Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China.
- 2. School of Basic Medical Sciences Chongqing, Chongqing Medical University, Chongqing 400016, China; Center for Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
- 3. Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing 400037, China.
- 4. School of Basic Medical Sciences Chongqing, Chongqing Medical University, Chongqing 400016, China.
- 5. The First Clinical Institute, Zunyi Medical University, Zunyi 563000, China; Zunyi Medical and Pharmaceutical College, Zunyi 563006, China.
- 6. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
- 7. Center for Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Medical School of Guizhou University, Guiyang 550025, China.
- 8. Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
- 9. Department of Hematology, Children's Hospital of Chongqing Medical University, Chongqing 401122, China.
- 10. Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
- 11. Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. Electronic address: [email protected].
- 12. Medical Center of Hematology, Institute of Science Innovation for Blood Ecology and Intelligent Cells, Xinqiao Hospital of Army Medical University, Chongqing 400037, China. Electronic address: [email protected].
- 13. Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) relapse and therapy resistance, predominantly through immune evasion. Here, we identify multimerin 1 (MMRN1) as being highly and specifically expressed in LSCs. Mechanistically, MMRN1 activates the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 1 (STAT1) pathway via its epidermal growth factor (EGF)-like domain, suppressing Neu5Ac degradation to drive sialylglycan accumulation, which forms glycoimmune checkpoints functionally akin to programmed death 1 (PD-1)/the cytotoxic T-lymphocyte antigen-4 (CTLA-4). These sialylglycans activate the sialylglycan-Siglec immune checkpoint axis, impairing T/natural killer (NK) cell activity and enabling LSC immune evasion. Additionally, MMRN1 sustains LSC self-renewal via the EGFR/STAT5/CD9 pathway. Genetic ablation of MMRN1 markedly suppresses AML progression and synergizes with anti-PD-L1/CTLA-4 therapy. In a clinical trial (ChiCTR2500097714), erlotinib (an EGFR Inhibitor) combined with azacitidine plus the HAG regimen, which consists of homoharringtonine, a low dose of cytarabine, and granulocyte colony-stimulating factor priming, achieves a remission rate of 75% in relapsed/refractory AML, likely via MMRN1/EGFR axis blockade. Our findings establish MMRN1 as a dual-functional target for LSC maintenance and immune evasion and propose that disrupting MMRN1 or EGFR remodels the immunosuppressive tumor microenvironment, offering a promising strategy for AML immunotherapy.
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Research Areas: Cancer
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