Faculty, Staff and Student Publications
Publication Date
4-11-2025
Journal
Nature Communications
Abstract
Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is mainly mediated by mutant, dysfunctional natural killer (NK) cells with impaired cytotoxic capability against cancer cells. Preclinical in vivo studies demonstrated that injecting NK cells from healthy donors efficiently depleted CCUS mutant cells while allowing normal cells to regenerate hematopoiesis. Our findings suggest that early intervention with adoptive cell therapy can prevent or delay the development of MDS.
Keywords
Myelodysplastic Syndromes, Killer Cells, Natural, Humans, Animals, Hematopoietic Stem Cells, Mice, Male, Female, Precancerous Conditions, Mutation, Tumor Escape, Clone Cells, Cancer, Medical research
DOI
10.1038/s41467-025-58662-0
PMID
40216768
PMCID
PMC11992119
PubMedCentral® Posted Date
4-11-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons