biostudies-literatureUnknownGeorge BMSontag FoundationBurroughs Wellcome FundMedical Research CouncilWellcome TrustDamon Runyon Cancer Research FoundationDamon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation)Max-Planck-GesellschaftImmunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offeNature biotechnologyhttps://www.ebi.ac.uk/biostudies/studies/S-EPMC7618518biostudies-literatureTreatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein.PMC7618518218481/Z/19/ZRG94424203151#74-23MR/X008371/1RG83195RG106133218481306752306752/Z/23/ZZaro BWLiu JEleftheriou Mde la Rosa JYu QYankova EGeorge BMBagri JStone RMNestola GCamargo FBaxter JRak JVolk RFEvans SSpiekermann MBapcum EMockl LLebedenko CGChai PHemberger HVassiliou GSAlmahayni KRussell JHuntly BJPTzelepis KDamaskou AFlynn RAPerr JGiotopoulos GfalseTreatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein.Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offe2025-01-01T00:00:00Z2025 Apr2026-07-14T17:28:21.851Z2026-06-23T03:09:40.634ZS-EPMC76185184026932110.1038/s41587-025-02648-2