Research conducted by Case CCC Molecular Oncology Program member Shujun Liu, PhD, Immune Oncology Program member William Tse, MD, MBA, and their team indicates a novel mRNA vaccine approach that targets fusion oncogenes—long considered “undruggable” due to a lack of conventional drug-binding sites despite their central role in oncogenesis—in acute myeloid leukemia (AML).
In the study, mRNA vaccination targeting AML1::ETO fusion gene eliminates leukemia cells via activating T cells, published in Leukemia on April 10, the researchers engineered a nucleoside-modified mRNA vaccine (EV-AE) designed to elicit immune recognition of AML1::ETO-expressing cells.
Delivery via EVs improved in vivo protein expression and avoided some limitations associated with lipid nanoparticle systems, including low delivery efficiency and toxicity concerns.
In immunocompetent murine models, EV-AE vaccination significantly reduced leukemic burden, lowered white blood cell counts, and extended survival compared to controls. Histopathologic analysis showed decreased leukemic infiltration across multiple organs without detectable toxicity.
Mechanistically, the vaccine activated antigen-presenting cells and T-cell responses, particularly CD4+ T cells, and induced cytokine signaling pathways central to tumor immunity. RNA sequencing and pathway analyses highlighted engagement of JAK-STAT, TNF, MAPK, and PI3K-AKT signaling, supporting coordinated immune-mediated tumor clearance.
While the findings are preclinical, the study establishes a proof-of-concept for targeting fusion-driven malignancies through mRNA vaccination. The authors note that broader application may extend to other cancers harboring chimeric oncogenes, with future work focused on optimizing durability, delivery, and translational relevance.