Treatment 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 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.
Authors
- Konstantinos Tzelepis (ORCID: https://orcid.org/0000-0002-4865-7648)
- Charlotta G. Lebedenko (ORCID: https://orcid.org/0000-0002-9891-9247)
- George Giotopoulos (ORCID: https://orcid.org/0000-0003-1390-6592)
- Peiyuan Chai (ORCID: https://orcid.org/0000-0002-9203-8975)
- Regan Volk (ORCID: https://orcid.org/0000-0001-6748-719X)
- Fernando D. Camargo (ORCID: https://orcid.org/0000-0002-5630-5909)
- George S. Vassiliou (ORCID: https://orcid.org/0000-0003-4337-8022)
- Malte Spiekermann (ORCID: https://orcid.org/0000-0001-5760-9333)
- Brian J.P. Huntly (ORCID: https://orcid.org/0000-0003-0312-161X)
- Leonhard Möckl (ORCID: https://orcid.org/0000-0003-1387-886X)
- Helena Hemberger (ORCID: https://orcid.org/0009-0007-4535-5859)
- Jaana Bagri (ORCID: https://orcid.org/0000-0002-2450-8226)
- Jonathan Perr (ORCID: https://orcid.org/0000-0002-0014-2565)
- Aristi Damaskou
- Justyna Rak (ORCID: https://orcid.org/0000-0002-9398-4947)
- E. Joanna Baxter (ORCID: https://orcid.org/0000-0002-5946-5238)
- Jorge de la Rosa (ORCID: https://orcid.org/0000-0002-0201-2078)
- Eliza Yankova (ORCID: https://orcid.org/0000-0003-2913-0012)
- Benson M. George (ORCID: https://orcid.org/0000-0003-4031-0954)
- Karim Almahayni (ORCID: https://orcid.org/0000-0001-6844-4327)
- Balyn W. Zaro (ORCID: https://orcid.org/0000-0002-8938-9889)
- Siân Evans (ORCID: https://orcid.org/0000-0002-2867-1688)
- Richard Maury Stone (ORCID: https://orcid.org/0000-0002-7526-2633)
- James Russell (ORCID: https://orcid.org/0000-0002-9431-8428)
- Ryan A. Flynn (ORCID: https://orcid.org/0000-0002-8529-3070)
- Gianluca Nestola
- Jie Liu (ORCID: https://orcid.org/0000-0003-3307-1975)
- Maria Eleftheriou (ORCID: https://orcid.org/0000-0002-1842-5838)
- Qi Yu (ORCID: https://orcid.org/0000-0002-7240-6478)
- Ece Bapcum
Institutions
- Boston Children's Hospital (US)
- University of California, San Francisco (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- California Institute for Regenerative Medicine (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- Max Planck Institute for the Science of Light (DE)
- Dana-Farber Cancer Institute (US)
- Jenner Institute (GB)
- Harvard Stem Cell Institute (US)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1038/s41587-025-02648-2
- Citations
- 16
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 12.90
Funders
- Burroughs Wellcome Fund
- Damon Runyon Cancer Research Foundation
- National Philanthropic Trust
- Wellcome
- Sontag Foundation
- Dana-Farber Cancer Institute
- Wellcome Trust
- UK Research and Innovation
- Leukaemia UK
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Max-Planck-Gesellschaft
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre