2. Academic Validation
  3. The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

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

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. gregor.reid@ubc.ca.
  • 7 Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. gregor.reid@ubc.ca.
  • # 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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