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<p>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.</p>

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Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月23日

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  • Benson M. George,
  • Maria Eleftheriou,
  • Eliza Yankova,
  • Jonathan Perr,
  • Peiyuan Chai,
  • Gianluca Nestola,
  • Karim Almahayni,
  • Siân Evans,
  • Aristi Damaskou,
  • Helena Hemberger,
  • Charlotta G. Lebedenko,
  • Justyna Rak,
  • Qi Yu,
  • Ece Bapcum,
  • James Russell,
  • Jaana Bagri,
  • Regan F. Volk,
  • Malte Spiekermann,
  • Richard M. Stone,
  • George Giotopoulos,
  • Brian J. P. Huntly,
  • Joanna Baxter,
  • Fernando Camargo,
  • Jie Liu,
  • Balyn W. Zaro,
  • George S. Vassiliou,
  • Leonhard Möckl,
  • Jorge de la Rosa,
  • Ryan A. Flynn,
  • Konstantinos Tzelepis

摘要

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.