RUNX1 upregulation and RUNX1-ETO depletion inhibits survival of t(8;21)-positive leukemia cells.

Background: t(8;21) acute myeloid leukemia (AML) is one of the most extensively studied AML subtypes, with the RUNX1-ETO fusion gene playing a crucial role in its pathogenesis. However, targeting this fusion gene alone has not yielded positive outcomes, likely because it fails to eliminate leukemia cells without restoring normal RUNX1 function. Objective: To enhance the therapeutic efficacy for this leukemia, we propose a novel strategy based on the pathogenic mechanism. We deliver RUNX1 small activating RNA (RUNX1‑saRNA) and RUNX1‑ETO small interfering RNA (RUNX1‑ETO‑siRNA) to RUNX1‑ETO‑positive AML cells, aiming to simultaneously silence the fusion gene and restore wild‑type RUNX1 expression. Methods: Kasumi‑1 cells were transfected with RUNX1‑saRNA and/or RUNX1‑ETO‑siRNA. The effects on apoptosis, autophagy, cell proliferation, and cell cycle progression were evaluated by Western blotting, CCK‑8 assays, and real‑time PCR. Results: Upregulation of RUNX1 promoted apoptosis and autophagy, inhibited proliferation, and blocked cell cycle progression. Similarly, downregulation of RUNX1-ETO produced comparable effects. The combined treatment resulted in enhanced effects compared with either intervention alone, with increased apoptosis and autophagy, and more pronounced inhibition of proliferation and cell cycle arrest. Conclusions: This combination therapy exerts potent cytotoxic effects on RUNX1-ETO-positive AML cells