Targeting oncogene-induced senescence in ETV6::RUNX1 pre-leukemic cells - PubMed
7 hours ago
- #ETV6-RUNX1
- #leukemia
- #senescence
- The t(12;21)(p13;q22) translocation generates the ETV6::RUNX1 (E::R) fusion gene, common in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
- ETV6::RUNX1 induces a pre-leukemic state with features of Oncogene-Induced Senescence (OIS), including slowed cell cycle and increased DNA damage markers.
- E::R expression leads to senescence-like phenotypes: altered morphology, increased β-galactosidase activity, elevated ROS, and SASP factor secretion.
- The p53 pathway is dysregulated in E::R+ cells, causing cell cycle arrest but impaired apoptosis, providing survival advantage under stress.
- Senolytics SSK1 and piperlongumine selectively target E::R+ cells via β-gal activity and ROS, while TM5441 induces apoptosis via PAI-1 upregulation.
- In Sca1-E::R transgenic mice, E::R-induced OIS was confirmed in pre-leukemic cells, with reduced colony formation post-SSK1 treatment.
- The study highlights E::R's dual role in OIS and apoptosis resistance, suggesting senescence-targeted therapies could prevent leukemia progression.