ArticleCell death discovery2026
Targeting oncogene-induced senescence in ETV6::RUNX1 pre-leukemic cells.
Article in Cell death discovery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
10 authors.
Funding
Abstract
The t(12;21)(p13;q22) is the most common chromosomal translocation in pediatric Bcell precursor acute lymphoblastic leukemia (BCP-ALL), occurring in 2-5% of healthy newborns. This alteration generates the ETV6::RUNX1 (E::R) fusion gene, encoding an aberrant transcription factor that is insufficient to directly cause leukemia, but establishes a clinically silent pre-leukemic progenitor not yet fully characterized. We previously showed that E::R expression in the murine pro-B BaF3 cells caused the slowdown of cell cycle progression and increased phospho-histone H2AX levels, both features of Oncogene-Induced Senescence (OIS). This study investigates E::R's ability to induce senescence in pro-B and immature hematopoietic cells, revealing new therapeutic targets for pre-leukemic cells. We observed that E::R caused a senescence-like phenotype in BaF3 cells, characterized by altered morphology, increased β-galactosidase activity, elevated reactive oxygen species (ROS) and Senescence-Associated Secretory Phenotype (SASP) factor secretion. It dysregulated genes within the p53 pathway, including senescence-related genes, causing the accumulation of p53 protein and alteration in its post-translational modifications. In E::R positive cells, while p53-mediated cell cycle arrest occurred, apoptosis was impaired, providing a survival advantage under genotoxic stress. Multiple therapeutic approaches targeting these vulnerabilities were tested. Senolytics SSK1 and piperlongumine selectively eliminated E::R+ cells by exploiting elevated β-gal activity and ROS levels, respectively. TM5441 leveraged caspase-3 inhibitor PAI-1 upregulation to induce apoptosis. Furthermore, using Sca1-E::R transgenic mice, we validated E::R-induced OIS in the pre-leukemic Lin-Sca1+ immature population and observed reduced pre-B colony formation after SSK1 treatment. These findings demonstrate E::R's dual role in inducing OIS and conferring apoptosis resistance, highlighting the potential of senescence-targeted therapies to prevent leukemia progression and relapse in E::R carriers.
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