Discovering a Novel Therapeutic Target: RNA-Binding Proteins Present on Cancer Cell Surfaces

In a groundbreaking leap for cancer biology and therapeutic innovation, a team of researchers led by Dr. Ryan Flynn at Boston Children’s Hospital, in collaboration with esteemed colleagues at the Cambridge Stem Cell Institute, has unveiled a remarkable discovery centered on a novel class of cell-surface RNA-binding proteins. Their work, recently published in Nature Biotechnology, introduces a powerful new avenue for targeting acute myeloid leukemia (AML) and certain solid tumors by exploiting the presence of nucleophosmin 1 (NPM1) on the surface of malignant cells. This approach not only breaks traditional paradigms of cancer cell targeting but offers hope for treatments that minimize harm to normal, healthy tissues.

Historically, the molecular landscape of cancer has posed enormous challenges, particularly in AML. This aggressive blood cancer exhibits a complex network of pathways essential not only to malignant cells but also to normal hematopoietic stem cells, thus creating a precarious therapeutic balance. Conventional drugs, albeit somewhat effective, often falter due to their inability to distinguish thoroughly between malignant and normal cells, resulting in substantial toxicity and poor patient tolerance. This scientific impasse has sustained an urgent demand for selective molecular targets—biomarkers that are expressed predominantly or exclusively on cancerous cells.

The Flynn group’s discovery capitalizes on an unusual feature: the ectopic localization of the RNA-binding protein NPM1 to the exterior of AML cells. While NPM1 traditionally functions within the nucleolus as a chaperone for ribosomal biogenesis and genomic stability, its aberrant expression on the cell surface of cancer cells marks a profound departure from its canonical role. Detailed investigations revealed that cell-surface NPM1 is dramatically upregulated in leukemic cells, with expression levels exceeding those found on healthy blood stem cells by over 100-fold. This significant differential creates a therapeutically exploitable target that, until now, remained concealed within the interior of the cell.

The team elucidated the mechanistic underpinnings of this phenomenon in the context of glycoRNAs—an emerging class of glycoconjugated RNA molecules residing on the cell exterior, which form organized clusters with RNA-binding proteins including NPM1. Prior foundational work has characterized these glycoRNA-protein complexes as novel signaling platforms modulating cellular communication with the microenvironment. This groundbreaking concept redefines the understanding of cell-surface biology, highlighting an uncharted molecular landscape ripe for targeted intervention.

Leveraging this insight, Flynn and colleagues engineered monoclonal antibodies specifically directed against NPM1 presented on the surface of AML cells. These antibodies demonstrated potent anti-leukemic efficacy across multiple preclinical in vivo models, selectively eliminating malignant cells while sparing normal hematopoietic populations. Such specificity is crucial as it addresses one of the most stubborn obstacles in AML treatment—the preservation of healthy bone marrow function during therapy. Notably, the antibodies also effectively targeted leukemic stem cells, the elusive subpopulation responsible for disease initiation, persistence, and relapse.

The impact of targeting leukemic stem cells cannot be overstated. These cells exhibit remarkable resistance to conventional chemotherapies and are often responsible for the clinical recurrence of AML. By attacking these cells head-on through a uniquely surfaced antigen like NPM1, the therapeutic paradigm shifts from merely controlling disease to potentially achieving durable remission or cure. In murine models, this strategy extended survival and markedly reduced disease burden, with no observed off-target toxicity, emphasizing the treatment’s clinical promise.

Beyond leukemia, the research explored the broader oncological relevance of cell-surface NPM1. Screening an extensive panel of 47 human and murine solid tumor models unveiled variable but significant expression of cell-surface NPM1 across many tumor types, including prostate and colorectal carcinomas. These findings suggest a wider applicability of NPM1-targeting antibodies, potentially expanding immunotherapy’s arsenal against notoriously treatment-resistant solid tumors.

The identification of NPM1 as a cell-surface antigen in solid tumors is particularly compelling given the historical difficulty of finding cancer-selective surface markers for these malignancies. Cancers like colorectal carcinoma have long evaded effective immune targeting due to the scarcity of unique markers distinguishable from normal tissue. The cell-surface presentation of NPM1 thus represents a potential ‘molecular handle’ for immune system engagement, a prospect that could reinvigorate therapeutic strategies for multiple cancers.

Crucially, the research underscores the newly appreciated biology of glycoRNAs and RNA-binding proteins as a rich source of tumor-associated antigens. The clustering of these molecules on the cell surface appears not to be a random occurrence but an orchestrated phenomenon potentially advantageous to tumor survival and immune evasion. The team’s future investigations aim to decode the biological imperatives underpinning the externalization of NPM1 and to identify additional molecular candidates within these clusters that could serve as targets or biomarkers.

The discovery that malignant cells co-opt an RNA-binding protein, traditionally intracellular, and mobilize it to the cell membrane hints at a novel tumor strategy that may confer advantages such as altered signaling, adhesion, or immune modulation. Understanding these dynamics will be critical to refining antibody-based therapeutics and possibly integrating them with other modalities, including cellular therapies and immune checkpoint inhibitors.

To translate these foundational findings into clinical impact, Boston Children’s Hospital has already pursued intellectual property protections domestically and internationally. This strategic move paves the way for the development of antibody therapies targeting NPM1, with the potential to enter early-phase clinical trials and ultimately offer new hope to patients with aggressive hematologic and solid malignancies.

The collaboration among interdisciplinary teams spanning molecular biology, oncology, immunotherapy, and structural biochemistry highlights the power of cross-sector partnerships in unearthing novel therapeutic targets. The convergence of expertise in glycoRNA biology, stem cell research, and antibody engineering illustrates a modern scientific approach to solving intractable problems in medicine.

In summary, Dr. Ryan Flynn’s team has illuminated a captivating facet of cancer biology—the aberrant cell-surface expression of an RNA-binding protein—and harnessed it into an actionable therapeutic target. By shifting the paradigm toward precision targeting of cancer stem cells with minimal collateral damage, their work charts a course for next-generation cancer therapies. As future studies delve deeper into the mechanisms and clinical translation, this discovery holds transformative potential for millions battling AML and other formidable cancers, marking a true milestone in the quest for safer, more effective treatments.

Subject of Research: Treatment of acute myeloid leukemia and solid tumors through targeting cell-surface RNA-binding proteins, specifically NPM1.

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

News Publication Date: 23-Apr-2025

Web References:
DOI: 10.1038/s41587-025-02648-2
Flynn Lab at Boston Children’s Hospital
Cambridge Stem Cell Institute

Keywords:
Cancer stem cells, RNA binding proteins, Myeloid leukemia, Gene targeting, Molecular targets, Stem cell therapy, Antibody therapy, Monoclonal antibodies, Cell surface receptors

Tags: acute myeloid leukemia therapyBoston Children’s Hospital studycancer biomarkers discoverycancer cell surface markersinnovative cancer biology researchminimizing toxicity in cancer treatmentnovel cancer treatmentsnucleophosmin 1 targetingRNA-binding proteinsselective molecular targetstherapeutic innovation in oncologytherapeutics for solid tumors