The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

  • Leukemia. 2024 Mar 22. doi: 10.1038/s41375-024-02221-x.
Ali Farrokhi  #  1 ,  Tanmaya Atre  #  1 ,  Jenna Rever  #  1 ,  Mario Fidanza  1 ,  Wendy Duey  2 ,  Samuel Salitra  1 ,  Junia Myung  1 ,  Meiyun Guo  1 ,  Sumin Jo  1 ,  Anuli Uzozie  1 ,  Fatemeh Baharvand  1 ,  Nina Rolf  1 ,  Franziska Auer  3 ,  Julia Hauer  3 ,  Stephan A Grupp  4 ,  Patrice Eydoux  2 ,  Philipp F Lange  1  2 ,  Alix E Seif  4 ,  Christopher A Maxwell  1  5 ,  Gregor S D Reid  6  7
Affiliations
  • 1. Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada.
  • 2. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 3. Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, Munich, Germany.
  • 4. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 5. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
  • 6. Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada. [email protected].
  • 7. Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. [email protected].
  • # Contributed equally.
PMID: 38519798 DOI: 10.1038/s41375-024-02221-x
Abstract

The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Eμ-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Eμ-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Eμ-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse.

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