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 offer a general strategy for detecting and treating AML. Surface profiling and in vivo work also demonstrate csNPM1 as a target on solid tumors. Our data suggest that csNPM1 and its neighboring glycoRNA-cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.
Author Info: (1) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US
Author Info: (1) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. (3) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. (4) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (5) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (6) Department of Physics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. (7) Department of Physics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. Max Planck Institute for the Science of Light, Erlangen, Germany. (8) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (9) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (10) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (11) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (12) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (13) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (14) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (15) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (16) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (17) Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. (18) Max Planck Institute for the Science of Light, Erlangen, Germany. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (21) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (22) Department of Haematology, University of Cambridge, Cambridge, UK. (23) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (24) Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. (25) Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. (26) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (27) Max Planck Institute for the Science of Light, Erlangen, Germany. Faculty of Medicine 1, Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. Faculty of Sciences, Department of Physics, Friedrich-Alexander-Universitt Erlangen-Nrnberg, Erlangen, Germany. (28) Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK. Cambridge Institute of Science, Altos Labs, Cambridge, UK. (29) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. ryan.flynn@childrens.harvard.edu. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ryan.flynn@childrens.harvard.edu. Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. ryan.flynn@childrens.harvard.edu. (30) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Department of Haematology, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Wellcome Trust Sanger Institute, Hinxton, UK. kt404@cam.ac.uk.
