MMRN1-EGFR drives sialylglycan-Siglec immune evasion in AML leukemia stem cells.
other
Where this comes from
- Record sourced from PubMed, PMID 42030946.
- Also identified by DOI 10.1016/j.stem.2026.03.012.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
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.