Targeting oncogene-induced senescence in ETV6::RUNX1 pre-leukemic cells

  • Cell Death Discov. 2026 Mar 11;12(1):145. doi: 10.1038/s41420-026-03001-5.
Denise Acunzo  #  1 ,  Mayla Bertagna  #  1 ,  Giulia Risca  2 ,  Linda Beneforti  3 ,  Silvia Bresolin  4  5 ,  Stefania Galimberti  2  6 ,  Isidro Sánchez-García  7  8 ,  Andrea Biondi  1 ,  Giovanni Cazzaniga  9  10 ,  Chiara Palmi  1
Affiliations
  • 1. Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
  • 2. Bicocca Bioinformatics, Biostatistics and Bioimaging Centre (B4), School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
  • 3. Tettamanti Center, Monza, Italy.
  • 4. Pediatric Hematology, Oncology and Stem Cell Transplant Division, Women and Child Health Department, Padua University and Hospital, Padua, Italy.
  • 5. Onco-Hematology, Stem Cell Transplant and Gene Therapy, Istituto di Ricerca Pediatrica Foundation - Città della Speranza, Padua, Italy.
  • 6. Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
  • 7. Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
  • 8. Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain.
  • 9. Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. [email protected].
  • 10. School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy. [email protected].
  • # Contributed equally.
PMID: 41813667 DOI: 10.1038/s41420-026-03001-5
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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